Coronavirus
Structural Task Force

Where are the drugs?

Why are vaccines developed so quickly and treatments so slowly?

In March 2020, the WHO declared COVID-19 a pandemic. Since then, 14 vaccines have entered the global market[1], and the number of immunized people grows every day. Even though vaccine development has never been this fast in history and will save many lives worldwide, people are still getting infected. To save patients afflicted with severe cases of COVID-19 and prevent health care systems from collapsing, effective drug treatments are the next step. But shouldn’t there already be drugs available?

What is the difference between vaccines and drug treatments?

While vaccines protect non-infected people from future infections, drugs help sick people. They alleviate symptoms and shorten the time to recuperate. Vaccines are important to combat a disease in the long run, through reaching herd immunity and protecting risk groups that would otherwise not survive an infection. Drugs, however, are equally important to fight acute infections.

How are vaccines developed?

First, scientists study the pathogen and its way of causing a disease in detail. Researchers then present a part of the virus that can be targeted by a vaccine for further investigation. This first lab stage is called the "research & discovery stage". What follows are pre-clinical trials, which are carried out in animals or cultured cell lines. Here, scientists prove that their vaccine candidate can cause an immune response and is not toxic.

If all data collected until this point looks promising, a clinical trial to test the vaccine in humans follows:

  • Phase I examines the safety and dose for the vaccine, as well as the immune response.
  • Phase II tests safety, efficacy, dosing, and immune response in a larger and more diverse group of people.
  • Phase III tests the vaccine on thousands of subjects to determine efficacy and side effects.
  • If successful, the vaccine is approved by the FDA in the US or the EMA in the EU. After approval, the vaccine is monitored in the real world, and more data is collected.
Phases of a clinical trial overview. Source: https://lupustrials.org/about-trials/phases-of-a-trial/
Figure 1: Phases of a Clinical Trial, taken from https://lupustrials.org/about-trials/phases-of-a-trial/.

How come it progressed so fast for the coronavirus?

On January 10th, 2020, the genome of SARS-CoV-2 was published by a consortium of Chinese and Australian scientists[2]. This started global efforts to develop vaccines. For the first time, corporations, governments, and scientists from academia worked together on this scale to end the pandemic. The first vaccine approved in the western world was Pfizer-BioNTech in December 2020 (approved in the EU[3] and the US[4]). It took eleven months, a record time never reached for any other vaccine in history.

The fastest vaccine developed before COVID-19 was the mumps vaccine in the 1960s[5]. It took only four years to develop, which is amazingly fast compared to the average 10 years it takes for a vaccine to progress from basic research to approval[6]. Given this info, how was it possible to get SARS-CoV-2 vaccines ready in less than a year?

First, SARS-CoV-2 did not come out of nowhere, entirely. For years scientists have been studying its relatives SARS and MERS, their way of infecting cells, their proteins, and genetics[7]. Because of that, scientists did not have to start from scratch with researching these matters for the new coronavirus. Of course, there are differences, but the viruses’ general framework shows many similarities.

The cost of developing a vaccine, on average, surpasses the 1-billion-dollar mark[8], with a lot of the money spent on candidates that turn out to be failures. For many infectious diseases, funding simply cannot be sustained throughout development, especially if the disease is rare or occurs only locally. This was not a problem for the development of SARS-CoV-2 vaccines. Massive funding from governments and companies gave scientists more than enough resources to test their vaccine candidates. Also, because of all these resources, the developers were able to run several stages of testing in parallel[9].

Probably the most interesting reason for having vaccines this fast are the new vaccine technologies that have been developed since the turn of the century: mRNA and vector vaccines. Scientists often refer to them as vaccine platforms because they are technologies into which you only need to insert the part that is specific to a virus. For this, you need the virus’ genetic information, which was published early in this pandemic. Vaccine developers then inserted SARS-CoV-2 into their systems and were ale to quickly procede with the trials.

In the past, inactivated viruses or isolated viral proteins were used in vaccines. These, however, are highly specific to the virus you are trying to fight. This means, it was necessary to start at a basic level again every time a new vaccine was developed. Researchers hope that through these new vaccine platforms, the time for vaccine development in general will be a lot shorter in the future.

How is drug development different and why does it take so long?

The development of a new drug takes years, too. Generally, the timelines for drug and vaccine development show similar steps: Research & discovery, pre-clinical and clinical trials, approval and monitoring also apply for drug development.

Reaching the approval of an effective drug costs around $1,335.9 million[10], and failures are possible at every step of the way—like promising candidates from the pre-clinical stages showing no effect in humans, etc.

However, when comparing modern drug development to the new vaccine platforms, we can see just how much more complicated it is. Antiviral drugs are molecules that interact with parts of the virus and block it from entering a cell, stop it from replicating or stop another vital step of the infection path. There are also drugs that interact with parts of our own immune system to stop the disease from escalating.

Structurally, a drug candidate has to exactly fit its target, which is often a protein. This triggers two problems: What target should be chosen and what should the drug molecule look like.

Nowadays, millions of molecules are screened for their interaction with viral targets. This is done through computerized models but still takes a lot of time. Once there is a lead structure—a potentially effective molecule—, it is tested in pre-clinical trials and optimized structurally. During optimization, many hundreds of similar molecules are compared to see if their properties improve.

Different approaches to develop a drug take different amounts of time. One shortcut to developing an effective treatment is the repurposing of an already approved drug or a shelved candidate. The second fastest way is to develop a therapeutic antibody, followed by classic screening for a new drug.

Repurposing drugs for new diseases

Reusing drugs or drug candidates that have already been evaluated for safety greatly shortens the development time. It is even better when an already approved drug or a drug that is already backed with significant data from human trials shows an effect on the new disease.

An example for this is the first HIV medication AZT. It was first developed in 1964 as a potential cancer therapy, but later was found not to be very effective. In the 1980s, it was included in a screening for AIDS treatment and was found to interfere with HIV’s replication. It was later shown to decrease the death rate in people with AIDS and subsequently approved for treatment[11].

Remdesivir—a dead end?

Remdesivir is an antiviral drug that was designed to interfere with the replication of the genome of RNA-based viruses. The drug was first developed as a potential treatment for hepatitis C and respiratory syncytial virus and was later tested against the Ebola virus[12], which did not lead to convincing results[13].

But what do COVID-19 studies with remdesivir say?

The EU and US approved this medication in 2020 based on trials with patients that had moderate or severe cases. One study found that hospitalized patients with moderate COVID-19 benefited from a 5-day treatment with remdesivir.[14] For severe cases, there is some evidence that remdesivir could shorten the time to recuperate better than a placebo[15].

But the WHO is now advising against using the drug based on a meta-analysis they did. This convinced the EMA to re-evaluate remdesivir and maybe even take back the approval in the EU[16]. In the WHO study, the effect of four repurposed COVID-19 treatments—including remdesivir—on 11,330 adults was examined[17]. In this analysis, remdesivir showed little to no effect on hospitalized patients with COVID-19, as indicated by overall mortality, need of artificial ventilation, and length of hospital stay.

The other repurposed drugs from the WHO analysis were hydroxychloroquine (a treatment used against malaria), Lopinavir (a protease inhibitor used against HIV), and interferon beta-1a (an immune modulating drug for MS treatment). None of these showed a beneficial effect against acute COVID-19.

Dexamethasone is a success

The most dangerous aspect of a COVID-19 infection is that the person’s immune system overreacts and attacks the body in addition to the virus. Steroids are often used to dampen an immune response, so the commonly available drug dexamethasone was tried as a treatment. This has proven to be highly effective and has now become part of the standard care for COVID-19 patients[18].

Other drugs currently under evaluation

Monoclonal antibody treatments are currently under review in the EU and US.[19] Their effect: When the antibody attaches to the spike protein, the virus cannot enter the body’s cells, depriving it of its means of replication. Some of these treatments are combinations of two different antibodies that can attach to different parts of the spike, in theory, binding it more effectively.

The three treatments currently in the EMA review pipeline are: bamlanivimab and etesevimab, REGN-COV2[20], and regdanvimab[21]. The FDA[22] has authorized several monoclonal antibodies for emergency use and they have been shown to be effective at reducing the symptoms of COVID-19 if administrated early in the course of the disease[23].

Antibodies can block SARS-CoV-2 infection. When antibodies are targeting the spike protein, it fails to bind to the human ACE2 receptor and cannot enter our cells. An infection is blocked. Alternationbased on Whittaker and Daniel (Natur, 2020).
Figure 2: Antibodies can block SARS-CoV-2 infection. When antibodies are targeting the spike protein, it fails to bind to the human ACE2 receptor and cannot enter our cells. An infection is blocked. Alternation based on Whittaker and Daniel (Nature, 2020).

Ongoing efforts

As there is more and more structural data available on SARS-CoV-2’s proteins, there are also more interaction studies with potential drug molecules and combinations.

Still, drug development takes time. In comparison to vaccines, which have just had a technology revolution, drugs will take longer from basic research to being ready for use. But there are already many different types of drugs under development, since funding is not a problem for COVID-19 treatments, and international collaboration speeds up the process as well.

Whether any of the current candidates will prove effective in treating COVID-19, remains to be seen. Maybe even a combined therapy with multiple drugs could be used to achieve the desired outcome.


[1] https://www.unicef.org/supply/covid-19-vaccine-market-dashboard

[2] https://virological.org/t/novel-2019-coronavirus-genome/319

[3] https://www.ema.europa.eu/en/medicines/human/EPAR/comirnaty

[4] https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/pfizer-biontech-covid-19-vaccine

[5] Tulchinsky, Theodore H.. “Maurice Hilleman: Creator of Vaccines That Changed the World.” Case Studies in Public Health (2018): 443–470. doi:10.1016/B978-0-12-804571-8.00003-2

[6]COVID-19 vaccine development pipeline gears up. Mullard, Asher. The Lancet, Volume 395, Issue 10239, 1751 - 1752

[7] Abdelrahman Zeinab, Li Mengyuan, Wang Xiaosheng. Comparative Review of SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza A Respiratory Viruses. Frontiers in Immunology 11 (2020). doi:10.3389/fimmu.2020.552909   

[8]Estimating the cost of vaccine development against epidemic infectious diseases: a cost minimisation study, Gouglas, Dimitrios et al. The Lancet Global Health, Volume 6, Issue 12, e1386 - e1396

[9] https://www.nature.com/articles/d41586-020-03626-1

[10] Wouters OJ, McKee M, Luyten J. Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018. JAMA. 2020;323(9):844–853. doi:10.1001/jama.2020.1166

[11] https://www.niaid.nih.gov/diseases-conditions/antiretroviral-drug-development

[12] https://www.gilead.com/-/media/gilead-corporate/files/pdfs/covid-19/gilead_rdv-development-fact-sheet-2020.pdf

[13] Pardo, Joe et al. “The journey of remdesivir: from Ebola to COVID-19.” Drugs in context vol. 9 2020-4-14. 22 May. 2020, doi:10.7573/dic.2020-4-14

[14] https://jamanetwork.com/journals/jama/fullarticle/2769871

[15] https://www.nejm.org/doi/10.1056/NEJMoa2007764

[16] https://www.ema.europa.eu/en/news/update-remdesivir-ema-will-evaluate-new-data-solidarity-trial

[17] Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results.  384, 497-511 (2020).

[18] https://www.covid19treatmentguidelines.nih.gov/immunomodulators/corticosteroids/

[19] https://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-covid-19/treatments-vaccines/treatments-covid-19/covid-19-treatments-under-evaluation

[20] https://www.ema.europa.eu/en/news/ema-starts-rolling-review-regn-cov2-antibody-combination-casirivimab-imdevimab

[21] https://www.ema.europa.eu/en/news/ema-starts-rolling-review-celltrion-antibody-regdanvimab-covid-19

[22] https://www.fda.gov/consumers/consumer-updates/know-your-treatment-options-covid-19

[23] https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibodies-treatment-covid-19-

Since the outbreak of SARS-CoV-2, infection has continued to spread. At the same time, governmental agencies around the world have adjusted the rules to prevent its spread. Information sources as basis for these rules have been obtained from scientific studies, public health research and simulation tests to understand the efficiency of mask types in preventing spread of infection by SARS-CoV-2. In this article, we will look at the mask types in use today, how much they can impede viral droplets and aerosols and how the construction of different masks helps to protect us from infection by SARS-CoV-2.

SARS-CoV-2 droplet sizes and viral transmission

The SARS-CoV-2 virus can be transmitted via droplets and aerosols. 

Droplets are particles of sizes varying from 0.05 to 500 μm. They are directly emitted while breathing or talking. After being released into the air, larger droplets fall to the ground and others rapidly evaporate to form droplet nuclei less than 5 µm of size, also called aerosols, containing viruses in the range of 0.02 to 0.3 μm. Droplet nuclei can remain suspended in air for a longer time compared to large droplets and potentially contribute to airborne transmission1,2,3.

SARS-CoV-2 has been observed to be transmitted via 3 modes:4,5,6

  •   Contact transmission (usually via direct contact with infected persons, surfaces, or air)
  •   Droplet transmission over short distances when a person is close to an infected person
  •   Aerosol transmission over longer distances via inhalation of aerosols that remain airborne and travel with the air

Although maintaining a safe distance from an infected or possibly infected person will prevent viral spread via direct contact and droplet transmission, maintaining a safe distance may not be able to prevent spread of infection through airborne aerosols. This is why it becomes even more important to wear a mask.

Mask types and structure

Surgical masks, also called medical face masks or mouth-nose protection (MNS), are disposable products that are normally used in clinics or in doctor's offices on a daily basis. They are made of special plastics with multiple layers. They have a rectangular shape with wrinkles so that the mask can adapt to the face. The front (outside) is often coloured, the back (inside) is not. The masks have ear loops and a wire noseband (see Figure 1).

Due to the shape and fit of most medical face masks, some of the breathing air can flow past the edges. Especially during inhalation, unfiltered breathing air can be sucked in. Therefore, medical face masks usually offer the wearer less protection against pathogenic aerosols than particle-filtering half-masks (FFP). Medical face masks, however, can protect the mouth and nose of the wearer from pathogen transmission via direct contact, for example with contaminated hands.

Since they are medical devices, their manufacturing and distribution must be carried out in accordance with medical device law. They must therefore comply with the legal requirements and the European standard EN 14683:2019-10. Only then can manufacturers mark the medical masks with the CE mark and distribute them freely in Europe. This is subject to supervision by competent authorities7.

Surgical mask, picture taken by CSTF.
Figure 1: A surgical mask.

Particle filtering half masks / filtering facepieces (FFP) are objects of personal protective equipment (PPE) within the framework of occupational health and safety. They protect the wearer of the mask from particles, droplets, and aerosols. When worn correctly, FFP masks are tightly attached and offer external and self-protection. Since the masks are disposable products as intended by the manufacturer, they should be changed regularly and disposed of after use.

FFP masks are produced either with or without an exhalation valve. Masks without exhalation valve filter both the inhaled air and the exhaled air over the mask surface and therefore offer both self-protection and external protection. Masks with valves offer less external protection because exhaled aerosols are not intercepted by the filter material but are only slowed down and swirled to a certain extent by the valve.

Like medical face masks, FFP masks must comply with clear requirements of laws and technical standards. In particular, the filter performance of the mask material is tested with aerosols in accordance with the European standard EN 149:2001+A1:2009. FFP2 masks must filter at least 94% of the test aerosols, for FFP3 masks the minimum is even 99% . They are therefore proven to provide effective protection against aerosols. The test standard, together with the CE mark and the four-digit identification number of the notified body, is printed on the surface of the FFP mask7.

FFP2 mask, picture taken by CSTF.
Figure 2: An FFP2 mask.

Mask standards

The table below shows the currently accepted standards for masks and how they are effective in filtering out bacteria as well as particles.

Table showing Filtration Capacity of Mask Standards
Table 1: Filtration capacity of mask standards, evaluated standards include bacteria filtration efficiency (BFE), particle filtration efficiency (PFE), and penetration of filter material (PFM).

Mechanisms of protection

Masks ensure protection from viral spread in three main ways1,5:

Flow resistance inhibits the momentum of exhaled droplets and the velocity of incoming airborne aerosols. This significantly reduces the risk of infection in the vicinity of an infected person, protecting third parties as well. This is afforded by surgical masks, FFP2/N95/KN95, or better particle filtering respirator masks.

Droplet filtration blocks out large droplets via gravity sedimentation, inertial impaction, and minimizing contact of hand to mouth, nose, or other facial canals with access to the respiratory tract. It is afforded by most kinds of masks.

Aerosol filtration reduces the spread of aerosols via interception, diffusion, and electrostatic attraction. Electrostatic effects likely result in charge transfer with nanoscale aerosol particles. It is afforded by FFP2/N95/KN95 or better particle filtering respirator masks.

At small aerosol droplet sizes in the range of 0.1 to 1 μm, the mask layers prevent particles from passing mainly by blocking movement of particles with the fibers in the filter layer and, hence, not allowing diffusion. For nanometer-sized particles, which can easily slip between the openings in the network of filter fibers, electrostatic attraction is the main way by which mask layers remove low mass particles, which are attracted to and bind to the fibers. This filtering of particles by electrostatic attraction is generally most efficient at low speed of the particles such as the speed of aerosols released by breathing through a face mask.

It is important to note that openings and gaps (such as those between the mask edge and the face) can compromise the performance. Findings indicate that leakages around the mask area can reduce efficiencies by ∼50% or more, pointing out the importance of a proper “fit”8.

Although a home-made fabric mask will at least offer some degree of protection against larger droplets and prevent access to facial features, it will not be very effective in protecting against respirable particles and droplets with a diameter of 0.3 to 2 μm, as these pass through the materials largely unfiltered5.

Thus, the inhalation of droplets containing viruses can be prevented by using a tight-fitting mask with particle filtering properties (self-protection). The FFP2/FFP3 mask type is very well suited to protect people from an infection by means of aerosol even when the environment is strongly contaminated with infectious droplets5.

How does mask structure affect filter particles?

For high filtration and blocking efficiency, the construction of masks layers is very important. Factors that contribute to this efficiency are these4,8:

Movement of droplets/aerosols is directly affected by interfiber spacing of the mask material and the number of layers. Combining layers of differing fiber arrangement to form hybrid masks uses mechanical filtering and may be an effective approach.

Electrostatic interaction impeding aerosol transmission is influenced by the type of mask material. Electrostatic attraction mainly affects the removal of low mass particles, which are attracted to and bind to the fibers. Leveraging electrostatic filtering may be another effective approach8.

The SEM pictures below show the structure and construction of mask fibers and give an insight into the factors that contribute to their high filtering and blocking efficiency.

An FFP2 mask combines layers featuring different spacing and fiber network types to form hybrid masks, employing both mechanical and electrostatic filtering.

Microscopic image of FFP2 mask layers, showing different droplet sizes in comparison
Figure 3: SEM image of FFP2 filter layer fibers showing an incoming pseudo droplet and aerosol. A pseudo aerosol, shown here as a yellow dot, is bound to the mask fiber due to electrostatic attraction and, hence, cannot pass through the mask due to electrostatic filtering. A pseudo droplet shown here in blue is larger than the interfiber spacing of the mask fiber and, thus, cannot pass through the mask due to mechanical filtering. Picture: Carl Zeiss GmbH | Coronavirus Structural Task Force.

Why are FFP masks superior? 

Surgical and respiratory masks are compliant to regulations that guarantee to fulfill certain standards (cf. Table 1). The superior protection of FFP masks stems partially from its filtering layer (cf. Figure 3), using electrostatic filtration to block smaller particles (~0.1 µm).

Conclusion

While maintaining a safe distance from an infected or possibly infected person will prevent spread of infection through direct contact and droplet transmission, maintaining a safe distance may not effectively prevent the spread of infection through airborne aerosols. This is where it becomes very important to wear a mask.

Masks offer self-protection and minimize transmission of potentially infectious exhaled droplets to the surrounding atmosphere. However, in some situations like closed rooms or highly contaminated places, only masks with high blocking and filtration efficiencies will offer this kind of protection, provided they are closely fitted to prevent air from flowing around the mask edges.


The authors would like to explicitly thank Carl Zeiss GmbH, who provided the microscopic images.


References

1.        Anand, S. & Mayya, Y. S. Size distribution of virus laden droplets from expiratory ejecta of infected subjects. Sci. Rep. 10, 1–9 (2020).

2.        Chirizzi, D. et al. SARS-CoV-2 concentrations and virus-laden aerosol size distributions in outdoor air in north and south of Italy. Environ. Int. 146, 106255 (2021).

3.        Lee, B. U. Minimum sizes of respiratory particles carrying SARS-CoV-2 and the possibility of aerosol generation. Int. J. Environ. Res. Public Health 17, 1–8 (2020).

4.        Sanchez, A. L., Hubbard, J. A., Dellinger, J. G. & Servantes, B. L. Experimental study of electrostatic aerosol filtration at moderate filter face velocity. Aerosol Sci. Technol. 47, 606–615 (2013).

5.        Kähler, C. J. & Hain, R. Fundamental protective mechanisms of face masks against droplet infections. J. Aerosol Sci. 148, (2020).

6.        Oct, U. COVID-19 Scienti c Brief : SARS-CoV-2 and Potential Airborne Transmission small particles that can move through the air The term “ airborne transmission ” has a specialized meaning in public health practice respiratory microbes The epidemiology of SARS-Co. 2019–2022 (2021).

7.        https://www.bfarm.de/SharedDocs/Risikoinformationen/Medizinprodukte/DE/schutzmasken.html                       Accessed 21 April 2021.

8.        Konda, A. et al. Aerosol Filtration Efficiency of Common Fabrics Used in Respiratory Cloth Masks. ACS Nano 14, 6339–6347 (2020).


COVID-19 vaccines were developed in record time and vaccination exercise is of course ongoing in most countries. Everyone is anxious to see the pandemic come to an end for things to return to normal. As of 23rd April 2021, more than 966 million doses have been administered worldwide [1], however, we have to remember that we do not live in a world where everyone is going to be vaccinated. Two questions are of importance here: Are the current strategies and measures in place adequate to contain the virus fast enough, and are there things that could be done differently for a faster sustainable outcome?  To this effect, I state a couple of opinions that I believe are quite essential.

Are there other effective strategies for the COVID-19 vaccination campaign that programme managers can adopt for better vaccination coverage?

We have vaccines that are up to 95% efficacious, but more than that is requires for a well-planned campaign to bring the pandemic to an end. When a campaign is well planned and a good approach is adopted, it helps a lot in yielding an expected outcome. These approaches stated below have not yet been well-practised in the course of this pandemic. I believe it will be beneficial for the vaccination programme managers to adopt them accordingly.

Barrier Analysis

This is a rapid assessment tool that project implementers can use to identify behavioural determinants to know why a promoted behaviour has not been absorbed or adopted. This approach was developed in 1990 by Tom Davis who found it very useful in behaviour change projects [2]. Barrier analysis is necessary considering the context of different countries. Until today, some health organizations have used this approach to have successful and impactful projects [3,4]. This approach involves the use of a structured tool to understand why a particular behaviour has not changed even though a reasonable amount of effort has been put into it. It helps you to know the behavioural determinants of a particular behaviour and what needs to be improved for a better outcome. With this, vaccine uptake can be promoted for better vaccination coverage.

Needs Assessment

Needs Assessment is the collection and analysis of information that relates to the needs of affected populations which will help determine gaps between an agreed standard and the current situation. It helps to determine the key activities for intervention. After the designed questionnaires have been administered, retrieved and analysed, the actual area of focus will be more evident before project implementation. This can help prioritise or improve the services offered to a patient for better acceptability. We have used this approach to implement a health care worker vaccination programme in 2016 and it was very successful and impactful [5]. It helped to determine specific behaviours, activities and actual high-risk areas (apart from the normal official statistics) before implementation.

Health behaviour theories that can also be adopted during implementation

Health Belief Model was developed in the 1950s by a group of U.S. Public Health Service social psychologists who tried to know why some disease detection and prevention programmes had few participants [6,7]. It is based on the construct that people are willing to change if they:

  • believe their susceptibility to a particular condition (perceived susceptibility),
  • believe that the condition may have serious effects (perceived severity),
  • believe the need to take action to reduce any negative effect or its severity (perceived benefits),
  • believe they can practice the behaviour without anything stopping them (perceived barriers),
  • are exposed to the things that make them remember to do the behaviour (e.g., posters, television advertisements, setting a reminder) (cue to action), or
  • believe in their ability to practise the behaviour (self-efficacy)

Theory of Planned behaviour assumes that behavioural intention is the most important determinant of behaviour. It says that behavioural intention is influenced by a person’s attitude towards performing a behaviour and by beliefs about whether individuals who are important to the person approve or disapprove of the behaviour (subjective norm) [7].

I do encourage vaccination project managers to employ any of these models for a fast and better outcome since pieces of evidence have shown the effectiveness on vaccine uptake [8].

How have vaccines been distributed?

As of 23rd April 2021, 01:25 CEST, more than 966 million doses have been administered across 172 countries in the world with the rate of 16.4 million doses daily. This is adequate to vaccinate only 6.3% of the global population [1]. More than 20 countries have not started vaccination at all, and they do not have the vaccines. The vaccine distribution has been so uneven when comparing the high-income and low-income countries. A considerable quantity of vaccines has been administered in the high-income countries and they have also booked more vaccines. As of 19th March 2021, high- and upper-middle-income countries have secured more than 6 million doses out of 8.6 billion expected to be produced. There is a very large margin between these two, high-income countries vaccinate 25 times faster than the low-income countries (ones that have been able to procure few vaccines). In Africa, the majority of the countries have doses that can only be enough for <1% of their total population. For example, Nigeria plans to vaccinate at least 70% of the eligible people aged 18 years and above in four phases within the next two years, but this is impossible with the rate they are going [9]. India (the world’s biggest maker of vaccines) usually supplies vaccines to low-income countries that cannot afford very expensive vaccines [10]. Now, India is experiencing a large COVID-19 surge (since April 2021), and they will have to stop some external supply for their use which will cause more shortage in all these low-income countries. This even makes it more difficult to quell the outbreak globally. It is understandable to prioritise one’s country, but we must remember that eradicating a disease is more than that, it is just “a flight away” and the virus will come back to one’s own country—if not a new variant. The fewer coronavirus cases we have globally, the less likely that new variants will emerge.

How do we maintain protection?

All the approved COVID-19 vaccines will protect you from severe infection, hospitalisation and death irrespective of the efficacy rate. From research, when one is infected with COVID-19 and recovered, the person will gain at least a 6-month protection—it varies from person to person [11–13]. New variants will keep emerging, but I believe that at some point, the variants will not be very strong anymore as vaccination continues. This is why we need to have a running immunization programme at regular intervals. Since we are not yet certain about how long the immunity offered by the vaccine will last and as new variants keep emerging, it will be nice for countries to establish Supplementary Immunization Activities (SIAs), especially for COVID-19.

SIAs is a programme put in place to complement vaccination and get more people vaccinated. It does not replace routine immunization. This is done to boost immunity and prevent emerging variants. In the case of COVID-19, I think it should be carried out annually or on an even shorter schedule.

How do we get more people vaccinated with COVID-19 vaccines?

The best way to reach herd immunity is through vaccination. Vaccination is always considered effective and successful when people are willing to receive the vaccines. You can manufacture the most efficacious vaccine, but when people have disinformation or contrary opinion in getting vaccinated, it is a wasted effort.

Religious and traditional leaders are vital for a successful roll-out of COVID-19 vaccines mostly in the developing world. Generally, these trusted leaders should be involved [4].

Also, mainly in the developed world, one of the major setbacks in vaccination is that people do not want to be told what to do, they see it as a form of violation to their freedom. Adopting the theories mentioned above can help deal with the major determinants of such behaviour.

Incentivising vaccination at this point is important—giving people a quality shirt (for example, with an imprint of their favourite leader) or likes, which they can proudly wear outside, can help spread awareness. When others see that this person has been vaccinated and “did not die”, they can re-consider getting vaccinated.

Other prevention strategies that need to be encouraged other than masking, hand-washing, and social distancing:

In disease prevention, it is always encouraged to observe any safe and effective measures first before thinking of medications or treatments, in order to protect yourself. It is not yet peer-reviewed or strongly proven that the vaccines protect you from spreading or contracting the virus—most especially the new variants—, and that is the reason you are always encouraged to employing masks and social distance. I must encourage these other preventive measures as well. 

Nasal irrigation and gargling: Nasal irrigation- is simply the practice of washing your nasal cavity to reduce mucus and germs. There may be a shred of limited clinical evidence on this for SARS-CoV-2 infection, nevertheless, other studies support this, and I agree with them [14,15]. This is usually performed by mixing salt and baking soda in lukewarm water, using it to flush your nostril. Please do keep any device you are using sterile and clean, anyway. A lot of people forget that it is important to wash your nose just as you wash your body mostly to prevent respiratory tract infections. Whenever I take a shower, I wash my nose and expel, it has drastically reduced my chances of getting an allergic reaction.

Opinion: Can the Strategy of the Ongoing COVID-19 Vaccination End the Pandemic Fast Enough? 1

Figure 1: A person performing nasal irrigation.

The study conducted in 1999 to ascertain the use of isotonic saline nasal irrigation among woodworkers, who face challenges due to the inhalation of dust particles, indicates that it significantly improves nasal symptoms. Also, more than half of the subjects continued to practise it after one year [16].

Gargling with warm saltwater can also help reduce the accumulation of mucus and germs in the upper respiratory tract [17,18].

Eating habit: Poor diet behaviour plays a vital role in disease prevention and management. You may wish to cook more often and stop eating junks or unhealthy food. I believe that eating food enriched with vitamins will help reduce the severity of illness. A well-nourished and hydrated (drink enough water) person is more likely to have a stronger immune response to fight infections.

Opinion: Can the Strategy of the Ongoing COVID-19 Vaccination End the Pandemic Fast Enough? 2

Figure 2: Unhealthy diets.

Elevator: People must be aware that elevators are not well ventilated. Viral droplets sneezed out can spread fast in there. You may wish to reduce the number of times you use elevators and always wear your masks inside the elevator.

Conclusion

Good strategies and planning are key to a successful vaccination programme, which is very important in tackling the ongoing pandemic. Some of the above-mentioned theories are worth considering for better vaccine uptake. Focusing on your country will not end the pandemic, and it will even affect the low-income countries negatively as they will find it more difficult to recover economically not just from the virus. There may be new variants of SARS-CoV-2 every year or more, but after a while, the variants will be less of a problem to deal with, as people get booster shots yearly for the next two or three years. Only one human virus (smallpox) has been eradicated in history using vaccination [19,20]. Hence, SARS-CoV-2 can be controlled to the point that it will not cause major disruption to our lives, and things will return to normal. Government and policymakers around the world should put in more effort to ensure that vaccines are supplied quickly across the globe.

References

[1] Bloomberg. More Than 966 Million Shots Given: Covid-19 Tracker. Bloomberg.com [Internet]. [cited 2021 Apr 23]; Available from: https://www.bloomberg.com/graphics/covid-vaccine-tracker-global-distribution/

[2] A Practical Guide to Conducting a Barrier Analysis [Internet]. [cited 2021 Apr 20]. Available from: https://pdf.usaid.gov/pdf_docs/PA00JMZW.pdf

[3] World Vision. BA Tabulation Tables and Results Summaries (by country). [Internet]. [cited 2021 May 25]. Available from: https://drive.google.com/drive/folders/1uUb_IWgw6Kk8wgWHFb3Yxr5kpyEDJaMk?usp=sharing

[4] Harris N. Faith leaders must play key role in COVID-19 vaccine roll-out [Internet]. World Vision. [cited 2021 Apr 20]. Available from: https://www.worldvision.org/about-us/media-center/faith-leaders-must-play-key-role-in-covid-19-vaccine-roll-out

[5] Arogundade L, Akinwumi T, Molemodile S, Nwaononiwu E, Ezika J, Yau I, et al. Lessons from a training needs assessment to strengthen the capacity of routine immunization service providers in Nigeria. BMC Health Serv Res. 2019 Sep 14;19(1):664.

[6] Wong MCS, Wong ELY, Huang J, Cheung AWL, Law K, Chong MKC, et al. Acceptance of the COVID-19 vaccine based on the health belief model: A population-based survey in Hong Kong. Vaccine. 2021 Feb 12;39(7):1148–56.

[7] National Cancer Institute- Theory at a Glance [Internet]. [cited 2021 Apr 26]. Available from: https://cancercontrol.cancer.gov/sites/default/files/2020-06/theory.pdf

[8] Chu H, Liu S. Integrating health behavior theories to predict American’s intention to receive a COVID-19 vaccine. Patient Educ Couns [Internet]. 2021 Feb 17 [cited 2021 May 4]; Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889032/

[9] Joint press statement by NPHCDA, WHO and UNICEF on the arrival of COVID-19 vaccine in Nigeria [Internet]. [cited 2021 May 26]. Available from: https://www.unicef.org/nigeria/press-releases/joint-press-statement-nphcda-who-and-unicef-arrival-covid-19-vaccine-nigeria

[10] Serum Institute of India. About Serum Institute Of India Pvt. Ltd. [Internet]. [cited 2021 May 8]. Available from: https://www.seruminstitute.com/about_us.php

[11] Hall V, Foulkes S, Charlett A, Atti A, Monk EJM, Simmons R, et al. Do antibody positive healthcare workers have lower SARS-CoV-2 infection rates than antibody negative healthcare workers? Large multi-centre prospective cohort study (the SIREN study), England: June to November 2020. medRxiv. 2021 Jan 15;2021.01.13.21249642.

[12] Dan JM, Mateus J, Kato Y, Hastie KM, Yu ED, Faliti CE, et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science [Internet]. 2021 Feb 5 [cited 2021 Apr 26];371(6529). Available from: https://science.sciencemag.org/content/371/6529/eabf4063

[13] Abu Raddad LJ, Chemaitelly H, Malek JA, Ahmed AA, Mohamoud YA, Younuskunju S, et al. Assessment of the risk of SARS-CoV-2 reinfection in an intense re-exposure setting [Internet]. Epidemiology; 2020 Aug [cited 2021 May 26]. Available from: http://medrxiv.org/lookup/doi/10.1101/2020.08.24.20179457

[14] King D, Mitchell B, Williams CP, Spurling GK. Saline nasal irrigation for acute upper respiratory tract infections. Cochrane Database of Systematic Reviews [Internet]. 2015 [cited 2021 Apr 26];(4). Available from: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006821.pub3/full

[15] Panta P, Chatti K, Andhavarapu A. Do saline water gargling and nasal irrigation confer protection against COVID-19? Explore (NY). 2021;17(2):127–9.

[16] Rabone SJ, Saraswati SB. Acceptance and effects of nasal lavage in volunteer woodworkers. Occup Med (Lond). 1999 Aug;49(6):365–9.

[17] Ramalingam S, Graham C, Dove J, Morrice L, Sheikh A. Hypertonic saline nasal irrigation and gargling should be considered as a treatment option for COVID-19. J Glob Health [Internet]. [cited 2021 Apr 26];10(1). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193539/

[18] Satomura K, Kitamura T, Kawamura T, Shimbo T, Watanabe M, Kamei M, et al. Prevention of upper respiratory tract infections by gargling: a randomized trial. Am J Prev Med. 2005 Nov;29(4):302–7.

[19] Greenwood B. The contribution of vaccination to global health: past, present and future. Philos Trans R Soc Lond B Biol Sci [Internet]. 2014 Jun 19 [cited 2021 Apr 26];369(1645). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024226/

[20] World Health Organization. Smallpox [Internet]. [cited 2021 Apr 26]. Available from: https://www.who.int/health-topics/smallpox#tab=tab_1[

There is a secret code that virologists use to talk about the new coronavirus. This code is made up of synonymous words and abbreviations for each of the 28 proteins which facilitate the viral life cycle. In this article, we will shed some light on this mythical language.

First of all, SARS-CoV-2 has three classes of proteins:
Structural Proteins, namely the spike protein, the membrane protein and the envelope protein as well as the nucleocapsid, which forms an extra shell around the single-stranded RNA, are also known as the S-, M-, E- and N-Protein.

Non-structural proteins (NSP) ensure the viral life cycle but are not making up the hull or nucleocapsid; These are conveniently numbered 1–16.

And then there are accessory proteins, which seem to be more important in-vivo than in-vitro, and most of them have not yet been structurally determined.

Of course, this nice and clear naming scheme tells you little about the function and properties of the different proteins, which is why virologists invented plenty of other names for them. And this is where the confusion begins.


SARS-CoV-2 Pl2Pro meme
Meme by Andrea Thorn.


NSP3, for example, contains two ubiquitin-like (UBL1 and UBL2) domains, a papain-like protease (PLpro, PL2pro) domain (which includes a zinc finger), a "macro" domain (also known as X domain, Mac1, or ADP ribose phosphatase), a hypervariable region (also called Glu-rich acidic domain or HVR), two transmembrane domains (TM1 and TM2), an ecto (3Ecto) domain (which is also a zinc finger), a conserved domain of unknown function called Y1, and a coronavirus-specific carboxyl-terminal (CoV-Y) domain. The SARS-unique domains, or SUDs—namely SUD-M, SUD-N, and SUD-C—were all renamed after it was found out they are not unique to SARS: SUD-N is now Mac2, SUD-M is Mac3 and SUD-C is called DPUP.

If this was not enough to convince you that all of this is confusing, here are some additional names:

Spike:
S-Protein, surface glycoprotein, E2 glycoprotein

NSP1: leader protein

NSP5: 3CLpro, SARS-CoV-2 3C-like protease, 3C-like proteinase, main protease, NSP5A_3CLpro, NSP5B_3CLpro, Mpro, Non-structural protein 5

NSP9: Non-structural protein 9, ssRNA-binding protein

NSP10: Non-structural protein 10, growth factor-like protein, GFL

NSP12: RNA Polymerase, RNA-dependent RNA Polymerase, NiRAN, RdRp

NSP13: NSP13-pp1ab, non-structural protein 13, helicase, NTpase, Hel

NSP14: NSP14A2_ExoN, SARS-CoV-2 3'-to-5' exonuclease, non-structural protein 14, NSP14B_NMT

NSP15: NSP15-A1, SARS-CoV-2 endoRNAse, NSP15B-NendoU, NendoU, uridylate-specific endoribonuclease NendoU

All these names are certainly hard to remember, but as a scientist you need them in order to save the world! So, we made a handy glossary for you that you can access here.

If you have any more suggestions or corrections for the glossary, please let us know in the comments!

In addition to mRNA vaccines, another type of vaccine is employed against COVID-19: Vector vaccines—like the one from AstraZeneca—contain a mostly functioning virus. But how do they work exactly? What are their strengths and weaknesses? And finally, are they safe?

The novel mRNA vaccines against SARS-CoV-2 have caused some controversy, and many concerns have been raised. According to these, the vaccine has not been sufficiently tested, long-term effects are yet unknown, the vaccine might affect the patient’s genetic material.

While mRNA vaccines enfold the genetic material in a tiny lipid particle, so-called viral vector vaccines put it in a viral shell that functions as a transporter (vector). A large number of vaccines of this type are under development, and they are all based on various strains of the same virus known for causing the common cold. The European Medicines Agency (EMA) recommended the Oxford–AstraZeneca vaccine for approval in late January, and the United States approved the use of a similar vaccine from Johnson & Johnson in February. Why?

Viruses are transporters for genes

Viruses are not considered living organisms because they have no metabolism of their own. They contain only the genes that cause the host cell to produce new viruses.

In the evolution of viruses, some of their skills have become exceptionally refined. Viruses can specifically infect host cells, escape the host’s immune defenses, and insert their genetic material into the host cell. Once molecular biologists recognized these capabilities, scientists could turn viruses into tools that do not cause disease through genetic engineering. As modified tools, they are referred to as viral vectors.

Viruses as tools

To make viruses useful for research purposes, they are modified. Their natural genes must be changed or deleted. What is left in the end is a transporter that can be used to introduce desired genes into a host. This method is used, for example, to produce transgenic (genetically modified) plants or cell lines. In this process, researchers usually keep some natural functions of the virus such as the capability to invade host cells.

Viruses as vaccines

What exactly must be changed to turn a virus into a vaccine?

In order not to cause a disease, the virus must lose its ability to multiply inside the body. Viruses without the ability to reproduce are called "replication-deficient". In the past, replication was disabled via lengthy cell culture techniques but, since the 2000s, genetic engineering has made it possible to selectively remove or modify genes of a virus to stop it from reproducing. Removing critical genes can completely prevent reproduction of the virus and any chance of reversion to the pathogenic (disease-causing) variant can be prevented [3].

Gene modification can also be used to introduce structures such as the spike gene of SARS-CoV-2 into a virus that is harmless to humans. This addition turns the virus into a vaccine.

Viruses have been used as tools for a long time. Viral vectors were first described in 1972 [1]. In the early 1990s, gene transfer was first used for therapy through an attenuated adenovirus as vector [2].

Across the last twenty years, a number of vaccines based on viruses have been developed. An example of an approved vector vaccine is the Ebola vaccine Ervebo [4]. Because there is no treatment for Ebola to date, the epidemics from 2013 to 2020 were devastating for Central Africa. Mortality rates ranged from 25 to 90% [5]. In August 2018, Ervebo was used for the first time to vaccinate a large group of people. It proved to be highly effective [6] and was also licensed for employment in the EU in 2019 [5].

Different forms of virus-based vaccines, illustration produced by the WHO
Different forms of vaccines containing viruses. Left: The pathogen has been killed, but the immune system still recognizes the surface and reacts to it. Middle: The virus has had its ability to reproduce weakened, so it no longer causes serious disease. Right: Certain genes of a pathogen have been inserted into a viral vector; this is a harmless and attenuated virus. Source: WHO, https://www.who.int/news-room/feature-stories/detail/the-race-for-a-covid-19-vaccine-explained.

How does the AstraZeneca vaccine work?

This vaccine is known as AZD1222 (also called ChAdOx1 nCoV-19) [8]. It is an adenovirus that is similar to a pathogen for the common cold, but this strain was originally found in chimpanzees. It has been modified to be replication-deficient. AZD1222 was also modified to contain the coronavirus’ surface protein (spike) gene [9]. This chimpanzee virus is used because most people’s immune systems are familiar with adenoviruses that infect humans, and their immune systems might respond to those viruses before they can infect cells and produce spike protein. In comparison, the chimpanzee virus is unfamilar to the human immune system and is hence capable of infecting a cell [10]. Side effects can occur, but they do not stem from the actual disease. Feeling unwell after being vaccinated is triggered by our immune system fighting against an intruder.

AZD1222 invades some human host cells just like a usual common cold virus. During this process, the vector transports the gene of the spike protein into the host cell. The spike DNA is utilized by the cell to produce spike protein. This spike protein acts as an antigen, a substance that triggers an immune response. The immune system recognizes it as foreign and starts attacking, antibodies are produced and the few "infected" cells containing AZD1222 genetic material are destroyed. Antibodies bind to the antigen like pieces of a puzzle and hold on to it. The antigen-antibody clumps are then degraded.

What remains from the whole process are memory cells that recognize the spike protein when attacked by the real SARS-CoV-2. Previous training with the vaccine makes the next immune response faster and more effective. This prevents disease before it can break out.

Mechanism of viral vector vaccination
Development and effect of an adenovirus vector vaccine. Infographic: Katharina Hoffmann/Coronavirus Structural Task Force.

How effective and safe is the vaccine?

AZD1222 has already been tested in over 20,000 people across three phases of clinical trial [11]. Since its approval, data has been continued to be collected and combined into additional studies. Through these, it is possible to investigate possible side effects even more thoroughly since millions of people are being vaccinated and observed in the "real world".

One example is a British study on efficacy in people over 70 years of age. The result: A single dose of AstreZeneca’s viral vector vaccine or BioNTech’s mRNA-based vaccine is effective against a symptomatic Corona infection in 60-75% of cases. The likelihood of hospitalization is reduced by 80% with either vaccine [12].

The first nationwide study took place in Scotland. It was led by the University of Edinburgh and collected data from 5.4 million vaccinated people. Preliminary data show that AstraZeneca’s single-dose vaccine prevented a severe course—requiring hospitalization—in up to 94% of cases [13].

Through these real world studies, it is now known that the vector vaccine shows greater effectiveness with a larger interval between the first and second dose. Therefore, these studies recommend an interval of twelve weeks [14].

In terms of side effects, some data has already been collected on AZD1222 in the UK due to the earlier start of vaccination [15]. Common side effects experienced by one in ten patients receiving vaccination include:

  • tenderness, pain, warmth, itching, or bruising at the injection site,
  • feeling generally unwell or tired,
  • chills or feverish feeling,
  • headache,
  • nausea, and
  • joint pain or muscle soreness.

These frequent side effects are similar to those of the BioNtech vaccine. However, no serious side effects have been detected in the trials. Fever or flu-like symptoms are less common and are a general sign of the vaccine activating the immune system and therefore taking effect. In any case, these symptoms are not comparable to the risks of a severe COVID-19 course.

The EMA is currently looking into cases of blood clotting that occurred shortly after an AstraZeneca vaccination. So far there are no indications that the vaccine is unsafe. The frequency of blood clots in vaccinated people is not higher than it generally is in the population. According to AstraZeneca [15.1] the risk of pulmonary embolism, deep vein thrombosis (DVT) or thrombocytopenia is not higher in people receiving the vaccine compared to the general public. Among 17 million vaccinated patients in Europe, some are expected to suffer from these diseases, but it is very likely not linked to the vaccine.

What is in the vaccine?

In addition to the modified adenovirus, the vaccine contains several other substances [16].

Most are additives that stabilize the vaccine and make administration easier. These include amino acids, stabilizers, alcohol, sugar, salt, binders, and water. In addition, the vaccine is free of food allergens (such as soy or lactose) and contains no ingredients of human or animal origin. That sounds incredible for a chimpanzee virus that needs a host to reproduce. How can this be?

All modifications and amplification of the virus took place in a human cell line used in the laboratory for such purposes, so-called HEK293 cells. These cells are, however, not part of the vaccine.

What are the advantages of this type of vaccine?

Viral vector vaccines—just plain RNA/DNA vaccines—can be developed very quickly. The reason: As soon as the genes of the pathogen are known, they can be used for vaccine development. This shortens the time until clinical trials can begin. This makes vector vaccines suitable for sudden epidemic outbreaks [18].

One advantage of the AstraZeneca vaccine is its dosage. Oxford–AstraZeneca initially tested different dosing approaches for their vector vaccine. Vaccinations with two standard doses at intervals of four to twelve weeks and a vaccination with only one dose were compared. For this, a standard dose contains 5x1010 virus particles [19].

"By using a more effective dosing regimen," said Professor Pollard, the lead scientist at Oxford, "more people could be served with the same amount of vaccine."[20]. The ideal regimen was found to be the administration of a half dose (2.2x1010 virus particles) followed by a standard dose at least one month apart. The efficiency in this case was 90% [21]. However, this must first be confirmed by additional data. So far, vaccination is done with two standard doses.

Conclusion

In nature, viruses have perfected the ability to insert their genetic material into hosts. The fascinating abilities of viruses can nowadays be used by scientists. They are therefore used to create genetically modified plants or cells, to treat hereditary diseases, and to produce vaccines.

Vector vaccines—such as AstraZeneca’s—contain harmless and non-reproducing viruses that contain a part of a disease-causing virus. By artificially "infecting" the patient with the vector vaccine, the immune system is trained to respond to the pathogen and can react more quickly and effectively in the event of a real infection in the future.

[1] Jackson D.A., Symons R.H., Berg P. Biochemical method for inserting new genetic information into DNA of Simian Virus 40: Circular SV40 DNA molecules containing lambda phage genes and the galactose operon of Escherichia coli. Proc. Natl. Acad. Sci. USA. 1972;69:2904–2909. doi: 10.1073/pnas.69.10.2904.

[2] Zabner, Joseph et al. 1993 Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis Cell, Volume 75, Issue 2, 207 – 216.

[3] Using directed attenuation to enhance vaccine immunity, Rustom Antia, Hasan Ahmed, James J Bull, bioRxiv 2020.03.22.002188; doi: https://doi.org/10.1101/2020.03.22.002188

[4] https://www.who.int/vaccine_safety/committee/topics/ebola/Jul_2019/en/

[5] https://www.ema.europa.eu/en/news/first-vaccine-protect-against-ebola

[6] https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32621-6/fulltext#seccestitle160

[7] https://www.nature.com/articles/d42859-020-00016-5

[8] https://www.ema.europa.eu/en/documents/product-information/covid-19-vaccine-astrazeneca-product-information-approved-chmp-29-january-2021-pending-endorsement_en.pdf

[9] https://jvi.asm.org/content/jvi/77/16/8801.full.pdf

[10] https://www.cdc.gov/vaccines/covid-19/hcp/viral-vector-vaccine-basics.html

[11] https://clinicaltrials.gov/ct2/show/NCT04516746

[12] https://www.medrxiv.org/content/10.1101/2021.03.01.21252652v1

[13] https://www.ed.ac.uk/files/atoms/files/scotland_firstvaccinedata_preprint.pdf

[14] https://www.rki.de/DE/Content/Kommissionen/STIKO/Empfehlungen/AstraZeneca-Impfstoff.html

[15] https://www.gov.uk/government/publications/regulatory-approval-of-pfizer-biontech-vaccine-for-covid-19/information-for-uk-recipients-on-pfizerbiontech-covid-19-vaccine#side-effects

[15.1] https://www.astrazeneca.com/media-centre/press-releases/2021/update-on-the-safety-of-covid-19-vaccine-astrazeneca.html

[16] https://www.astrazeneca.at/content/dam/az-at/pdf/2021/Vaccine%20guide%20for%20HCPs%20-%202021-02-02.pdf

[17] Draper, S., Heeney, J. Viruses as vaccine vectors for infectious diseases and cancer. Nat Rev Microbiol 8, 62–73 (2010). https://doi.org/10.1038/nrmicro2240

[18] https://www.frontiersin.org/articles/10.3389/fimmu.2018.01963/full 

[19] https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3777268

[20] https://www.astrazeneca.com/media-centre/press-releases/2020/azd1222hlr.html

[21] https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32661-1/fulltext

Introduction:

Vaccination is a great means of achieving public protection against diseases. The main goal of any vaccine manufacturer is to produce a vaccine that will be safe and effective in preventing the target disease. Before any vaccine is rolled out for mass vaccination or campaign, it must have met the required rigorous scientific and ethical standards, ensuring safety, efficacy, purity, and potency (1). A vaccine is considered safe and effective when used correctly, leading to a successful vaccination campaign. However, from the general health point-of-view, vaccines are not risk-free and there are occasionally Adverse Events Following Immunization (AEFI) (2). The risk is of course outweighed by the benefits of vaccines as they protect us from vaccine-preventable diseases. Here, I will discuss the safety measures vaccination undergoes for it to be a success.

What does vaccination mean?

Vaccination is a simple, safe, and effective way of protecting people against harmful diseases, before they come into contact with them (3).

What is vaccination safety?

This entails the absence of preventable harm to the recipient, health care worker and the society at large during and after vaccination.

What are the stages of vaccine development before vaccination?

Vaccine development starts with the assessment of public health needs and priorities which progresses to scientific research on the target disease, pre-clinical and eventually, clinical trials (4). The following are the stages of vaccine development:

Research stage; involves the identification and isolation of the target antigen.

Pre-clinical stage; the potential vaccine is being tested on cells and animals after a careful examination.

Clinical trials (three phases); if the vaccine is safe in animals, it will then be suggested to be tested in human volunteers.

The clinical trials are usually in three phases.

  • Phase 1; trials involve a smaller number of people of about twenty to hundred healthy volunteers, this is designed to test and determine vaccine safety, doses, immune response (immunogenicity) and route of administration.
  • Phase 2; starts after the successful completion of phase 1. This may involve hundreds of volunteers with double-blind (the researchers and the research volunteers do not know if the research volunteers are in the vaccine group or the placebo group, to prevent bias) studies with a placebo-control group. It further tests safety and the amount of dose to provoke an immune response.
  • Phase 3; hundreds to thousands of volunteers are given the vaccine in comparison with the placebo group. It involves a randomized double or single-blind (the research volunteers do not know whether they are in the vaccine group or the placebo group, to prevent bias), placebo-controlled group (inactive substance, sometimes another type of vaccine is given to the research volunteers) to evaluate more on the vaccine safety, efficacy and side effects.

This is then followed by regulatory review, approval and manufacturing. After the product is rolled out, a surveillance system is established for continuous monitoring of the vaccine, immunization coverage and possible adverse reactions for risk-management (4,5). COVID-19 vaccines underwent these processes as well.

Who is responsible for vaccine approval?

Following scientific, ethical and international standards, approval on clinical trials, results, and licensing are done by the national and regional regulatory authorities in the countries where vaccines are manufactured (6). This must be guided by principles of fairness, transparency and accountability to ensure safety.

How are vaccines stored and handled?

Cold chain, sometimes referred to as “Supply chain” is the system used for storing vaccines in good condition. In the cold chain system, the levels designed to keep vaccines within recommended temperature ranges, from the point of manufacture to the point of administration differ. This means that the storage temperature range for every level may differ provided the potency of the vaccine is maintained. Vaccines can be sensitive to freezing or light but all vaccines are sensitive to heat. This is what the Vaccine Vial Monitor (VVM) on the vial helps to monitor. VVM is a chemical indicator label attached to the vaccine container (vial and ampoule) by the vaccine manufacturer which helps to monitor the temperature of a vaccine and ensure that no heat-damaged vaccine is administered. If the colour of the inner square is the same colour or darker than the outer circle, the vaccine has been exposed to too much heat and should be discarded. All vaccines must be discarded after the expiry date or six hours of opening. The recommended diluent is used for the reconstitution of freeze-dried vaccines before use.

Are some vaccines made for some persons?

Vaccination is carried out based on dosage, age group or sex. This is because there is a specific group of people used during the clinical trials who will determine the first target group to be vaccinated when the vaccine is rolled out. Notwithstanding, other group of people may still receive the vaccine as the vaccination goes on once safety is ensured. Please always check the fact sheet for any vaccine you wish to receive on the manufacturer`s website for such updates.

cdc-qIR77o5woJ8-unsplash
Figure 1: A good vaccination session. Photo by CDC on Unsplash

How are injection devices disposed of after a vaccination session?

Injection equipment can pose danger to the environment if not well disposed of, leading to environmental pollution. When needles and syringes are thrown into the bodies of water, they cause contamination to the environment and injury to the wildlife. Safety boxes are sharps waste containers that needles cannot penetrate, they are used to keep the used needles and syringes temporarily during a vaccination session. It is disposed of immediately after vaccination sessions to maintain safety. Appropriate use of a safety box is necessary to avoid needle-stick injuries (when the skin is pricked by needles accidentally) to the health care worker or other individuals. Special incinerators are used to burn these needles and syringes to minimise the toxic release into the environment.

Vaccination Safety Management 3
Figure 2: Unsafe disposal of used needles and syringes (Sharps).
Source: Adobe Stock

Vaccination Safety Management 4
Figure 3: Safe disposal of used syringes and needles (Sharps) in a safety box.
Source: Adobe Stock

What is Adverse Events Following Immunization (AEFI)?

This is any untoward medical occurrence which follows immunization and which does not necessarily have a causal relationship with the usage of the vaccine. AEFI can be vaccine product-related, vaccine quality defect-related, vaccination error- related, vaccination anxiety-related or a coincidental event.

Some minor vaccine reactions-AEFIs, you need to know:

  • Pain, redness, swelling at the site of injection
  • Irritability, malaise
  • Slight fever
  • Slight headache
  • Mild muscle pain
  • Loss of appetite
  • Joint pain
  • Lymphadenopathy (swollen lymph nodes, it can be under the armpit in the same arm of injection, etc.)

Some rare and severe vaccine reactions-AEFIs, you need to know:

  • Febrile seizures (convulsions that occur usually in children as a result of high body temperature)
  • Thrombocytopenia (low platelet count in the blood which usually helps to stop bleeding when one gets injured)
  • Anaphylaxis (severe allergic reaction)
  • Sterile abscess (swelling in the injection site usually occurs when an injection is not completely absorbed into the skin which makes pus build up in the tissue)
  • Difficulty in breathing
  • Encephalopathy (damage to the brain, affecting one`s mental state)
  • Persistent inconsolable crying or screaming

Severe AEFIs are rare, however, every AEFI must be reported to the health care worker or appropriate authority.

Before receiving any vaccine, please discuss with the vaccination provider about all of your medical conditions such as:

  • past and present allergic reactions
  • current fever
  • if you are taking blood thinner medications
  • if you have any bleeding disorder
  • if you are immunocompromised
  • if you are on a medication that affects your immune system
  • if you are pregnant or plan to become pregnant very soon
  • if you are breastfeeding
  • your previous vaccination history (7,8).

What does surveillance (pharmacovigilance) mean?

Pharmacovigilance is a part of the surveillance system designed to detect, assess, understand, respond and preventing adverse drug reactions, including reactions to vaccines-AEFIs in every country. Both national and international levels have surveillance systems for good monitoring and immediate actions in response to AEFIs. This helps to ensure the safety of vaccines even as vaccination is ongoing (2).

Conclusion:

Vaccines follow many rigorous scientific processes before and after being approved to ensure safety and effectiveness. Vaccination is safe when no harm is posed to the patient, health worker and society (avoiding pollution and injuries through proper disposal of injection wastes). If a vaccine requires a subsequent dose, you must receive the same type of vaccine as the initial dose. Always keep your vaccination card for the next visit and follow your vaccination schedule. It is encouraged to not go for a second dose of vaccine if you had a serious allergic reaction or side effect after the first dose. Discuss your medical history with the vaccination provider before taking a vaccine. Please wait for some time after receiving your vaccine for a little safety monitoring before going home. Vaccines work!

References:

1.         Centers for Disease Control and Prevention. U.S. Vaccine Safety - Overview, History, and How It Works | CDC [Internet]. 2020 [cited 2021 Mar 4]. Available from: https://www.cdc.gov/vaccinesafety/ensuringsafety/history/index.html

2.         World Health Organization. WHO Vaccine Safety Basics [Internet]. [cited 2021 Mar 3]. Available from: https://vaccine-safety-training.org/overview-and-outcomes-1.html

3.         Vaccination_World Health Organization. Vaccines and immunization: What is vaccination? [Internet]. [cited 2021 Mar 3]. Available from: https://www.who.int/news-room/q-a-detail/vaccines-and-immunization-what-is-vaccination

4.         Centers for Disease Control and Prevention. Ensuring Vaccine Safety | CDC [Internet]. 2020 [cited 2021 Mar 3]. Available from: https://www.cdc.gov/vaccinesafety/ensuringsafety/index.html

5.         Mitchell VS, Philipose NM, Sanford JP. Stages of Vaccine Development_Institute of Medicine (US) Committee on the Children’s Vaccine Initiative: Planning Alternative [Internet]. The Children’s Vaccine Initiative: Achieving the Vision. National Academies Press (US); 1993 [cited 2021 Mar 3]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK236428/

6.         World Health Organization_ Vaccine Safety. Vaccines and immunization: Vaccine safety [Internet]. [cited 2021 Mar 3]. Available from: https://www.who.int/news-room/q-a-detail/vaccines-and-immunization-vaccine-safety

7.         Moderna. Emergency Use Authorization (EUA) | Moderna COVID-19 Vaccine [Internet]. https://www.modernatx.com/. [cited 2021 Mar 16]. Available from: https://www.modernatx.com/covid19vaccine-eua/

8.         Pfizer-BioNTech. Pfizer-BioNTech COVID-19 Vaccine | cvdvaccine.com [Internet]. [cited 2021 Mar 16]. Available from: https://www.cvdvaccine.com

“The coronavirus has led to a worldwide crisis for over a year. In a new study, nanoscientist Prof. Dr. Roland Wiesendanger illuminates the origins of the virus. His findings conclude there are a number of quality sources indicating a laboratory accident at the Wuhan Institute of Virology as the cause of the current pandemic.”

This is the beginning of an official press release from the University of Hamburg. Unfortunately, this study is not a study at all, but a rather confusing piece of internet research. And because we, the Coronavirus Structural Task Force, conduct research at the very same University of Hamburg, we would like to comment on the press release and this "study".

Screenshot der "Studie"
Pages from the publictaion (R. Wiesendanger / UHH)

Here are the main arguments of the author, Roland Wiesendanger:

#1: Failure to identify the interim host proves that the disease is not of animal origin.

“In contrast to early coronavirus-based epidemics such as SARS and MERS, the scientific community has yet to identify the interim host that made the transmission of SARS-CoV-2 from bats to humans possible. Thus, there is no sound basis for a zoonotic theory as a possible explanation for the pandemic.” That an interim host of a zoonosis is not immediately identified is not unusual. The route of transmission of SARS-CoV was not elucidated until more than three years after the SARS pandemic ​[1]​; for MERS, which was first described in 2012, it took two years [2] and to date some information is still missing ​[2–4]​. Evidence indicates that interim hosts for SARS-CoV-2 may have been snakes, turtles, or pangolins ​[5–7]​. Furthermore, transmission between humans and various animal hosts has been demonstrated several times (which, for example, unfortunately led to the culling of many mink)​[8]​. The lack of knowledge of an intermediate host does in no way disprove zoonosis as a cause.

#2: SARS-CoV-2 is so adapted to humans that it could not have arisen naturally

“The SARS-CoV-2 viruses are astonishingly effective at binding to human cell receptors and infecting human cells, thanks to its special cell receptor binding domains combined with a special (furin) cleavage site of the coronavirus spike protein. This is the first time a coronavirus has had both of these characteristics and indicates a nonnatural origin of the SARS-CoV-2 pathogen.”

The ability of the virus to bind to human cells with the spike protein is not evidence that this was artificially produced. Influenza, HIV, and Ebola are also all very good at binding to human cells ​[9]​ - the latter two have been shown to be animal-derived (zoonotic) pathogens. All of these viruses possess a furin cleavage site. Furins are enzymes found in all vertebrates that allow viruses to better target vertebrate cells. Thus, it is not unusual for SARS-CoV-2 to have evolved such a site through natural mutation and selection. In fact, it occurs naturally in many other coronaviruses as well ​[10]​.

The receptor binding domains S1 and S2 are highly variable because it is exactly domains that enable specific binding to host cells - the new mutations that are currently causing us so much trouble display variations right here. Mutations in this domain arise due to selection pressure in humans (or other hosts) and are also not indicative of a non-natural origin ​[11,12]​.

What also speaks against the virus being completely man-made, is that the sequence of the virus does not fit known methods for artificially producing genetic material ​[13,14]​. Furthermore, designing a coronavirus would be considerably costlier than designing many other viruses because the genome is so large. This however, does not exclude the virus originating from a "gain-of-function" study.

Ausschnitt aus Animation, wie das Virus an die Wirtszelle bindet
Scene from animation showing how the virus binds a host cell; the virus is at the upper edge with spikes in green; ACE2 receptors are shown in purple. To see the whole animation, please click here. (Picture: Janet Iwasa / University of Utah and Coronavirus Structural Task Force)

Here it is perhaps worth noting that Professor Wiesendanger authored the study alone and is himself a non-specialist ​[15]​. He has never published on Corona before, and therefore it is understandable that he is unfamiliar with both the details of genetic engineering and the technical terminology.

#3: Bats do not fly 2000km

“There were no bats for sale at the wet market in the center of Wuhan, which is the suspected hub of the outbreak. The Wuhan Institute of Virology, however, houses one of the largest collections of bat pathogens in the world, taken from distant caves in southern Chinese provinces. It is extremely unlikely that bats naturally made their way to Wuhan, from almost 2,000 km away, to then start a worldwide pandemic in the immediate vicinity of the Wuhan Institute of Virology.”

Considering that the thesis supported by WHO ​[16]​ is that there must have been an intermediate host, as is indeed also stated in the study and the press release (see 1.), the presence of bats near the first human vectors is not necessary. Many of the possible intermediate hosts were traded in the market in question. So far, there is no certainty that the pandemic originated there - research is still ongoing - but the absence of bats does not argue against zoonosis. The collection of bat viruses at the Center for Emerging Infectious Diseases in Wuhan does exist however. A researcher at this institute - Shi Zhengli - discovered that SARS originated from bats, and she conducted a systematic study of bat viruses from fecal samples in 2013, for example ​[17]​. While the samples in question have been found in a cave 2000 kms from Wuhan, the bat in question (Rhinolophus affinis) does occur far and wide, including 250 km from Wuhan, in Hunan province. Bats have long been considered the largest source of different coronaviruses and thus the greatest risk for their transmission to humans ​[18]​.

#4: Research on viruses as bioweapons was conducted in Wuhan

One research group at the Wuhan Institute of Virology had been researching the genetic manipulation of coronaviruses for many years with the goal of making these more infectious, more dangerous, and more fatal. This has been demonstrated by numerous publications.”

The publications cited in the study, for example this one ​[19]​, are indeed concerned with the recombination of bat coronaviruses with spikes that can bind to human cells. These were used to trace how the 2002/3 SARS pandemic originated - not to make the virus more dangerous. Such research has taken place elsewhere - with many strict safety measures and safeguards - for example in North Carolina ​[20]​.

#5: The virological institute in Wuhan was not secure.

“Safety measures were documented as being insufficient at the Wuhan Institute of Virology prior to the outbreak of the coronavirus pandemic.”

The laboratory in Wuhan is a Biosafety Level 4 laboratory ​[21]​, the highest level - there are only a handful of such laboratories in the world, of which two are in China. Such labs have strict access controls, you have to be able to hermetically seal them off, and they are under negative pressure to prevent pathogens from escaping; access is only through an airlock; all wastewater is chemically and thermally treated; a full protective suit has to be worn, and when leaving, the whole body has to be cleaned with soap. Of course, no laboratory is perfect, but safety is a paramount issue in such laboratories ​[21]​. Nature has written a special report on the lab in Wuhan that illustrates this. In the text, Prof. Wiesendanger argues with a serious article from the Washington Post that points to episodes of malpractice in the laboratory in Wuhan, but whose sources remain undisclosed. Another source, a Youtube video, supposedly proves the improper disposal of laboratory equipment. However, while garbage can be clearly seen, typical laboratory waste such as pipette tips, consumables and gloves, is missing. Furthermore, the Chinese text of the video does not mention the waste in any way, it is about whether and how one could get into the building. A second source ​[22]​ shows a bat allegedly being sampled without protective equipment. Parts of the video, which is about a new coronavirus in pigs, show the non-BSL-4 area of the lab. The new coronavirus in pigs is said to come from the bat species shown. Nothing in this video suggests biosecurity problems in the lab.

Bilder eines CCTV Videos zu Wuhan, Fledermäusen und Corona bei Schweinen
Scenes from the laboratory video by CCTV. Left: Photograph of a bat which can serve as intermediate host for corona in pigs. Right side: Take from the Insitute of Virology in Wuhan (Pictures: CCTV).

6. Authorities covered up a laboratory accident in October

“There are numerous direct indications that the SARS-CoV-2 pathogen is of laboratory origin and point to a young researcher at the Wuhan Institute of Virology as being the first person to be infected. In addition, there are indications that the SARS-CoV-2 pathogen emerged from the Wuhan Institute of Virology into the city of Wuhan and beyond. There are also indications that the Chinese authorities conducted an examination of the institute in the first half of October 2019.”

The "indications of an official examination in the first half of October" are based on an analysis of mobile phone location data that an external firm is said to have produced for the Pentagon to show disruption of laboratory operations and road closures. However, the report provides no concrete evidence and was therefore deemed insufficient by the intelligence community. Especially since some of the allegations could be directly refuted ​[23]​. Little can be found on the Internet about the young scientist, Yan Ling Huan, apart from a Twitter account, videos, and a rebuttal from the lab. The hypothesis that she was the first to be infected can therefore neither be proven nor disproven.

All in all, one cannot rule out the lab as the point of origin - research is being done on coronaviruses there - but the sources cited in this "study" are not evidence of that. Circulation of the virus before December cannot be ruled out either, but the publication does not present any robust evidence.

Additional notes

The main problem with this study is that it appears to have been written by the author alone and was not peer reviewed. This is particularly regrettable since the author emphasizes the importance of peer review on page 3. Apparently, discussion and especially media attention are very desirable, but peer review is not, which is why the "publication" was done on the Research Gate platform, where you can simply upload a PDF.

BILD Schlagzeile zu Pressemitteilung
This is what the results of a successful press release look like: Title page of the Germen newspaper Bild on the morning after the press release(19.2.2021). Picture by Springer-Verlag.

Other problems with the "study" are the poor readability and deficiencies in the evidence - this document is not only confusing, but also does not comply with good scientific practice. Sources include not only private communications and Twitter posts, but also content from the Alt-Right movement, such as an unrefereed study ​[24,25]​ from Steve Bannon's entourage, articles from the Epoch Times ​[26]​ or Summit News ​[22]​. The document is also full of contradictions – for example, the first patient is said to have fallen ill on the first of October 2019, but elsewhere it says that the pandemic is due to a laboratory accident between October 6 and 11, 2019. The use of colored markers in the text also does not necessarily contribute to readability and is uncommon in publications. It is not clear why such a highly decorated and well-known scientist as Prof. Wiesendanger considered such writing publishable or even a study; and, unlike many of his colleagues, he does not do research on the coronavirus.

Conclusion

What comes across as an invitation to debate is a rather disorderly and angled piece of internet research that does not correspond with good scientific practice. Many people who are against China, or who are simply looking for someone to blame for Corona, feel vindicated and the University of Hamburg backs this up.

It is good and right that professors at German universities can publish and research whatever they want ("Forschungsfreiheit"). But the fact that this article is published in close consultation with the president ​[15]​ but without peer review and in the name of the university does not cast a good light on the University of Hamburg, which is, after all, our very own scientific home. Our statements here are about the shortcomings of this press release as well as the paper, and are not intended as criticism of Prof. Wiesendanger personally; we deeply regret this press release. As scientists, we should educate, critically question - and allow ourselves to be questioned. For the last twelve months, we have been informing colleagues and the general public about ongoing corona research, taken care not to accept funding from potential influencers (e.g. the pharmaceutical industry), and carefully reviewed every blog post, no matter how small. Every day we respond to inquiries from people who are confused, afraid of corona or of the measures being put in place. We teach, educate, we answer questions.

And that is what we will continue to do.


I would like to thank Dr. Florian Platzmann, Dr. Sam Horrell, Dr. Yunyun Gao, Pairoh Seeliger, Lea von Soosten, Katharina Hoffmann, Joshua Ezika and Sabrina Stäb for their help writing this article. Their expertise in lab safety, public health care, mandarin, molecular biology and their comprehensive internet / literature research made this opinion piece possible.


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Introduction

The coronavirus pandemic hit the entire world and caused millions of deaths. More than fifty companies race towards developing a vaccine to stop the disease (1). Vaccination presents a lasting solution to this unfavourable situation, reducing the burden of Coronavirus (2). The first vaccine to be approved for emergency use is an mRNA-based vaccine (3,4). How does it work? Here, I will shed some light on this, but before we go into details, we need to discuss a little about vaccines and how a foreign substance provokes an immune response in the body (immunogenicity).

Early impact of vaccines on humanity

Vaccines have existed since 1796 and have saved millions of lives over the years (5,6). Vaccines need to be given orally, intramuscularly or subcutaneously to, stimulate the body for an immune response and generate lasting immunity.

How the body fights diseases

The human body works very hard to remove any foreign substance (potential pathogens). When pathogens, such as bacteria or viruses enter the body, they attack and spread, causing disease. The immune system fights these infections recognizing a part of the pathogen using white blood cells which consist primarily of macrophages, B-lymphocytes and T-lymphocytes (7). Macrophages are antigen-presenting cells that engulf pathogens and digest them. Macrophages present parts of the pathogens to the T-lymphocytes and B-lymphocytes. When the B-lymphocytes are activated, they produce antibodies that target specific pathogens and destroy them. Also, when the T-lymphocytes are activated by the antigen-presenting cells, they seek out and destroy any infected cell in the body. However, it takes a couple of days for the body to generate the antibodies to fight an infection. After recovering from an infection, the immune system can remember how it fought the infection and can quickly in the future, prevent reinfection by the same or similar diseases.  When the infection is gone, the body is left with the supply of memory cells called T-lymphocytes and B-lymphocytes that are responsible for this rapid intervention (7). Vaccines cause the same process but without a serious illness and often even without an infection. Individuals react to vaccines differently, some persons experience symptoms like swelling or redness at the injection site, low-grade fever, tiredness etc. These minor symptoms result as the body tries to build immunity against the disease, and it is your body`s healthy response. It would be no good and impracticable for the vaccine to cause the full-blown disease - instead, vaccines prime the immune system to jump into action should you ever encounter the real thing. 

Traditional vaccines

Traditional vaccines contain either an attenuated (live or weakened) virus, an inactivated virus, or even a piece of a viral protein that can produce the immune answer – a so-called antigen that does not cause an actual disease but still stimulates the body to produce antibodies to fight a real infection (8). It tricks the immune system into thinking that an infection has occurred and the immune system responds by producing antibodies against the virus (9). mRNA-vaccines, however, do not contain dead or live pieces of the virus – they contain the genetic instructions necessary for our cells to make copies of the antigen itself. So, what is mRNA?

What is mRNA?

mRNA is how our body encodes information from the genome that is to be used as blueprints to make proteins: In every human cell, we find a nucleus that contains our genome in the form of DNA. This DNA is transcribed into mRNA, which then can leave the nucleus and enter the rest of the cell. DNA itself cannot leave the nucleus and this protects the cell’s genome from damage and manipulation. Once outside the nucleus, the mRNA is translated into proteins which then fulfil all kind of work tasks in our cells – they make up our hair, break down our food, transport oxygen around our body (10,11). They pretty much do everything that makes us go.

An mRNA vaccine exploits this process: When the mRNA vaccine enters our cells, it effectively skips the transcription step (DNA to RNA) and goes straight to translation (mRNA to proteins) to produce antigenic proteins (10,12).

How do the SARS-CoV-2 mRNA-based vaccines work? 

The best antigen in the coronavirus SARS-CoV-2 – the bit which is recognized by the immune system – is the spike protein. The outside of the SARS-CoV-2 (Coronavirus) is carries these spike proteins, which the virus uses to enter human cells and cause an infection.

New mRNA vaccines contain messenger RNA which encodes the spike protein and as it enters the cell, the spike proteins are produced within the cell. The spike protein then migrate to the surface of the cell, where the immune system recognizes it as foreign and the body will produce antibodies to fight the infection. At this point, the process to produce immunity is the same as for any other vaccine. When infected again, the body can rapidly supply memory cells- T-lymphocytes and B-lymphocytes that remember how to attack a similar pathogen. So, when the real coronavirus SARS-CoV-2 (spike proteins and all) enters the body, the immune system remembers how it fought the formerly produced spike proteins and can easily fight off the infection.

What is in the vaccine and why do we use it?

mRNA-based SARS-CoV-2 vaccines contain the mRNA strands encapsulated in lipid nanoparticles (think soap bubble) to protect it from hot temperatures as well as degrading enzymes (13,14). After being injected intramuscularly, the protection offered by the lipid nanoparticles helps the mRNA to remain active/potent until it enters the cells and releases mRNA. 

There are some advantages to mRNA vaccines, and I think it can be expected that we will soon see more of them for other illnesses. The production of mRNA vaccine doses is much faster and cheaper than traditional vaccines since it does not require a long process of growing viral proteins in a cell or an egg which then needs to be deactivated or killed to produce the vaccine (15). Also, in mRNA vaccines there is never a complete virus, so contracting the disease is impossible, which can happen with live vaccines. Finally, should mutations occur, it is relatively straightforward to change the mRNA vaccine to contain this new mutation.

However, the storage temperature of an mRNA vaccine is a challenge: they need to be stored at a very low temperature to maintain its potency until it is ready to be used and this type of freezer is not available everywhere and makes transport difficult compared to a traditional vaccine (14,16).

Can an mRNA-based vaccine change my DNA? 

As the vaccine contains no so-called “reverse-transcriptase”, the spike mRNA cannot be converted into DNA. mRNA-based vaccines cannot even enter the cell’s nucleus. Hence, they are not able to change your DNA. They are just a messenger to produce the spike protein and the enzymes of the cell readily destroy them shortly afterwards. Also, the unfortunate cell itself is destroyed by the immune system once it displays the spike on the surface and the immune system has learned to recognize it.

Do I still need to wear masks?

Also, remember that after getting vaccinated, your body needs time to develop antibodies in sufficient quantities, so you can still contract Coronavirus even after being vaccinated. Hence, we need to maintain safety measures (social distancing, masking, handwashing etc) while allowing immunity to develop after being vaccinated. It is also still unclear what happens if an infected person is vaccinated, or in people who have no strong immune system (immunocompromised patients). “I have been vaccinated, can I now go, hugging and kissing on the street?” Sorry, you can’t. This is because you can still contract the virus even after being vaccinated: the body needs time to develop immunity against an infection. This is the main reason for jab-spacing as it enables the body to build an immune response.

Conclusion

Vaccines trigger the production of memory cells (T-lymphocytes and B-lymphocytes) to fight infections and can protect us from life-threatening diseases. The more people get vaccinated, the more likely we are to achieve herd-immunity, where even unvaccinated people are protected. A good example of herd-immunity is a burning bush. The fire keeps spreading but when it encounters a large space or a river, it stops spreading and the other side of the bush will not be affected. However, the space must be large enough to make this happen. Vaccinated individuals are like the large space or river, they help in stopping the spread of the disease to the unvaccinated hence, protecting the unvaccinated. Also, remember that for this kind of protection to occur, a sufficient number of individuals must have been vaccinated. There is no scientific basis to show that an mRNA-based vaccine can change your DNA. Developing an mRNA vaccine within a short period is a phenomenal advancement in science. As people are being vaccinated, every other protective measure is encouraged if we want to end this pandemic. We can only think of relaxing measures when the number of cases has considerably reduced. Stay safe and healthy, and together we are protected.

Acknowledgement

I would like to thank Dr Andrea Thorn, Dr Dale Tronrud, Dr Sam Horrell and Dr Yunyun Gao for their wonderful and helpful suggestions. Also, my thanks go to Dr Thomas Splettstoesser for making an image used for this post.

References

1.         Regulatory Affairs Professionals Society. COVID-19 vaccine tracker [Internet]. [cited 2021 Jan 10]. Available from: https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-vaccine-tracker

2.         Nature Communications. Vaccines work. Nat Commun [Internet]. 2018 Apr 24 [cited 2021 Jan 3];9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915378/

3.         FDA. COVID-19 Vaccines. FDA [Internet]. 2021 Feb 18 [cited 2021 Feb 19]; Available from: https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/covid-19-vaccines

4.         Mueller B. U.K. Approves Pfizer Coronavirus Vaccine, a First in the West. The New York Times [Internet]. 2020 Dec 2 [cited 2021 Feb 19]; Available from: https://www.nytimes.com/2020/12/02/world/europe/pfizer-coronavirus-vaccine-approved-uk.html

5.         World Health Organization. Vaccines and immunization [Internet]. [cited 2021 Jan 10]. Available from: https://www.who.int/health-topics/vaccines-and-immunization#tab=tab_1

6.         Thèves C, Biagini P, Crubézy E. The rediscovery of smallpox. Clinical Microbiology and Infection. 2014 Mar;20(3):210–8. 

7.         Vitetta ES, Berton MT, Burger C, Kepron M, Lee WT, Yin XM. Memory B and T Cells. Annual Review of Immunology. 1991;9(1):193–217. 

8.         Centers for Disease Control and Prevention. Basics of Vaccines | CDC [Internet]. 2019 [cited 2021 Jan 10]. Available from: https://www.cdc.gov/vaccines/vpd/vpd-vac-basics.html

9.         Sell S. How vaccines work: immune effector mechanisms and designer vaccines. Expert Rev Vaccines. 2019 Oct;18(10):993–1015. 

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Overview

During the Corona-dominated year 2020 scientists all over the world united and gathered as much information as possible to understand the exact mechanism behind the lifecycle of SARS-CoV-2.
The main question was: how can we stop the virus from invading the human cell and causing COVID-19? A focus in the quest to answer this question, was the SARS-CoV-2 entry mechanism. The group of Janet Iwasa contributes to this ongoing research process by providing a high-quality video animation of the SARS-CoV-2 entry into the human host cell. This current version of the entry animation has already been shown on PBS News (08.12.20) and we aim to improve it with your help in 2021 (see below)!

The Entry Animation

Click this Link to see the Entry Animation on YouTube.

This entry animation is a collection of current knowledge about the SARS-CoV-2 entry mechanism. What we know at this point is that the mechanism starts with the viral approach. An individual can be infected with SARS-CoV-2 after inhaling airborne viral particles. These viruses can then travel into the airways, where they may encounter host cells of the respiratory epithelium in the trachea and lungs.

As you can read in a previous blogpost, the Spikes (teal) are Corona’s key to invade the host cell and thus of great interest in terms of vaccination and therapeutic approaches against COVID-19. The Spike protein recognizes a specific receptor on the human host cell surface, called ACE2 (purple). Usually, the Spikes are very dynamic and able to undergo opening, closing and bending movements. But after binding to ACE2, the protein is locked into its open position.  Another protein on the cell surface, called TMPRSS2 (orange), can then come along and cut the Spike protein in a specific location. These segments of the Spike protein fall away, exposing a portion of the Spike protein which was previously hidden. 

The Spike protein is then able to undergo a series of dramatic conformational changes. During the first stage, the Spike protein inserts itself into the membrane of the cell. In the second stage, segments of the Spike protein zipper back on itself, forcing the membrane of the cell and the viral membrane to fuse. After fusion, the viral RNA is deposited into the host cell, where it will direct the cell to produce more virions. This process is known as post-fusion.

The Annotation Tool

Click this Link to use the Annotation Tool.

SARS-CoV-2 Entry Animation from Iwasa Group – a little Christmas Present to the Scientific Community 7
Figure 1: Annotation tool with the animation in the center, annotations from the Iwasa Lab on the left and Comments on the right.
SARS-CoV-2 Entry Animation from Iwasa Group – a little Christmas Present to the Scientific Community 8
Figure 2: How it looks like when you hover over the video.

In January, this will be supplemented with a tool so that the knowledge about the SARS-CoV-2 entry mechanism can be discussed interactively by scientists all over the world. This online platform will serve as a basis for scientific discussion by providing an annotation tool. Scientific users can set a pin at any point of the video and comment their suggestions, criticism or questions about the mechanism and the structure depictions (see Fig. 1 for a prototype). Based on these annotations, the Iwasa Group will improve the animation of the entry process to provide an up-to-date detailed representation of this key process. The resulting entry animation is not only addressed to scientists, but it is also used for public outreach and education.

Even though the entry mechanism is not entirely understood yet, it could already be depicted in the fantastic animation of the Iwasa Group. There are still a lot of details and additional information to be found out about this process. From January on, the annotation tool therefore will provide the opportunity to discuss this mechanism publicly.

Thanks to the Iwasa Group for this Christmas present!

Merry Christmas!

Introduction

It is known as VUI‑202012/01 or B.1.1.7 – the new mutation of the coronavirus Sars-CoV-2. It may be responsible for a sharply increased number of infections in the southeast of England (​1​), however, the scientific results leading to very strict lockdown measurements in the south of the UK, and travel restrictions across Europe are few and far between. Here, we have compiled what is known up until now.

On mutations

Mutations are normal in the evolution of life – and of viruses. If two similar viruses have infected the same cell, their genomes can become mixed-up, one of the reasons why animal influenza strains are considered so dangerous. This is also called recombination. Mutations can be caused by chemicals, radiation (including UV light) and errors during genome copying. A typical SARS-CoV-2 virus accumulates two amino acid changes per month in its genome — a rate of change about half that of influenza (​2​). This is because SARS-CoV-2 can repair RNA to some extent. But even so, this natural process led to thousands of mutations since the beginning of the pandemic. If they affected the virus life cycle negatively, that strain may have likely died out - if they did not make a difference or enhanced its chances of survival, it may have persisted.


Nextstrain interface as of 22/12/2020: Mutations happen a lot. Screenshot by Andrea Thorn / Coronavirus structural Task Force.
SARS-CoV-2 mutations as of 22/12/2020: Mutations happen a lot. A very good interface to the genetic variants of SARS-CoV-2 is https://nextstrain.org/ncov/global. Screenshot by Andrea Thorn / Coronavirus structural Task Force.

Many mutations that are observed occur in the spike protein, which both serves to recognize potential host cells but is also what is being recognized by antibodies (i.e., the immune system).

Changes here can be crucial for the survival of the virus (“evolutionary pressure”) as they could significantly alter its affinity to the human receptor ACE2, which the virus uses as gateway to our cells.

Animation of spike protein binding the host cell and the molecular mechanism merging host cell and virus. CC-BY-NC Coronavirus Structural Task Force / Iwasa Lab

What vaccines do

Most, if not all, potential COVID-19 vaccines expose our body to some part of the spike protein, which can be made by the body itself (mRNA vaccines) or carried by a harmless virus instead of SARS-CoV-2 (vector). Our body then produces antibodies which specifically recognize the spike and persist for several months. If we are exposed afterwards to the real virus, the body can recognize it immediately – and the risk of infection is much lower as the immune system swings into action immediately. Earlier this year, the spike mutation D614G (amino acid residue number 614 changing from aspartic acid (D) to glycine (G)) caused quite a stir in the media, and became the predominant form of SARS-CoV-2 (​2​, 3). However, if and in how far this was caused by natural selection is still debated (​3​). Another example which triggered an increased media coverage was the mutation Spike Y453F, which originated from infected minks in Denmark (​4​) and led to a culling of millions of animals. In any case, if we would be vaccinated with a spike protein form that would be different from the one in a virus we encounter later, there is a small chance that the vaccine may be rendered ineffective. This chance is, however, small for SARS-CoV-2, in any case much smaller than for HIV, which famously evaded any attempt to develop a vaccine.

Model of spike (green) with bound antibody (yellow). Both models can be 3D printed (Instructions).  Photo CC-BY-NC 2020 Andrea Thorn / Coronavirus Structural Taskforce.
Model of spike (green) with bound antibody (yellow). Both models can be 3D printed (Instructions). Photo CC-BY-NC 2020 Andrea Thorn / Coronavirus Structural Taskforce.

What do we know?

There was a steep rise in infections in the UK recently, as in most other European countries.

A new mutation of the virus has emerged and seems to replace the old version of SARS-CoV-2 (​5​). Thousands of patients have been found to carry this variant.

This new variant has more mutations at once than expected. These mutations have not observed in this combination before.

The variant has been reported in the UK, the Netherlands, Denmark, Australia and Belgium so far.

What is striking to me as scientist about these findings is one thing in particular: How could the British government find that thousands of people were having the new SARS-CoV-2 variant, instead of the old, if the illness does not look any different? Sequencing samples from each and every patient would be technically very challenging, if not impossible. How could they know? The answer is:

Serendipity

The main PCR test employed in the United Kingdom is Thermo Fisher's TaqPathCOVID-19. This test identifies RNA on three different genome locations: In ORF1ab, nucleotide and spike. Now, it stopped working for the spike portion of the test, while the other two RNAs were still found to be present, which likely prompted scientists to sequence some of the samples in question. And indeed, the new mutant has a deletion of histidine-69 and valine-70, called 69-70del. This permitted easy differentiation of patients with the old SARS-CoV-2 (3 hits) and the new (2 hits) and is the reason why we know so much about the epidemiology of this variant!​*​ It has also to be said that this test is not used as often in other countries, such as Germany, and this could well be the reason why we do not know if and how widespread it is here. In addition, other countries sequence much smaller proportions of virus isolates than the UK, so ongoing circulation of this variant outside of the UK cannot be excluded.

The details of the mutation

The new variant of SARS-CoV-2 VUI-202012/01 has 14 amino acid changes and three deletions affecting the genes for ORF1ab, spike and ORF8. One of these mutations (N501Y) occurs in the receptor binding domain and could lead to an increased binding affinity to the human ACE2. The 69-70 deletion has likely an immunological role and is the reason this mutant was detected so widely, as this RNA location is used for PCR tests. Another interesting mutation is the P681H, which is next to a furin cleavage site that has a biological significance in membrane fusion. These mutations could be responsible for the increased transmissibility. The effects of the other mutations aren’t fully investigated yet. Here is a list of the mutations which have been observed in the VUI‑202012/01 or B.1.1.7 variant:

T1001I in gene ORF1ab
A1708D in gene ORF1ab
I2230T in gene ORF1ab
SGF 3675-3677 deletion in gene ORF1ab
A1708D in gene ORF1ab
HV 69-70 deletion in spikeThe 69-70 deletion on the spike protein is a re-occurring mutation that has shown to often co-occur with other amino acid changes in the RBD (​6​, 7).
(1) Evasion to the human immune response and in association with other receptor binding domain changes (​1​)
(2) Immunological role (​8​)
(3) Leads to diagnostic failures which permit detection (see above, "Serendipity")
(4) Associated with immune escape in immunocompromised patients (​9(​8​))
Furthermore, the 69-70 deletion arose in multiple unrelated lineages and is associated with the evasion of the immune response (​9​). It is being hypothesized that this mutation undergoes a strong positive selection when exposed to convalescent plasma therapy in an immunocompromised human host (​7​).
Y144 deletion in spikeDeletion in the spike N-terminal domain (​9​)
N501Y in spikeOne of six key contact residues in the spike receptor binding domains, this mutation leads to an increasing binding affinity to human and murine ACE2 (​1​).
A570D in spikeMutation located at the spike receptor binding domain (​10​)
P681H in spikeThe P681H mutation is located directly next to the furin cleavage site. It is one of the four residues which are insertions when compared to closely related coronaviruses, creating a furin cleavage site in the spike protein between the spike S1 and S2 domains. This prompts the entry of the virus into respiratory epithelial cells as well as the transmission in animal models (​1​)
The S1/S2 furin cleavage site of SARS-CoV-2 is not found in closely related coronaviruses and has been shown to promote entry into respiratory epithelial cells and transmission in animal models (​9​)
T716I in spikeMutation in in the S2 domain
S982A in spikeMutation in in the S2 domain (​10​)
D1118H in spikeMutation in in the S2 domain (​8​)
Q27 stop in ORF8The Q27stop mutation in the ORF8 leads to the truncation of the ORF8, and as it only consists of 121 amino acids, the consequence might be a loss of function. These and the other mutations could be responsible for the increased transmissibility of the B.1.1.7 variant. In any case, this mutation truncates the ORF8 protein at residue 27 or renders it inactive which allows further downstream mutations to accrue. (​1​)
R52I in ORF8
Y73C in ORF8
D3L in nucleocapsid
S235F in nucleocapsid
picture of Spike mutation sites from the COVID-19 Genomics UK Consortium
Spike mutation sites. Picture by the COVID-19 Genomics UK Consortium (​9​).

Why were there so many mutations at once?

This could be a result of prolonged or chronical SARS-CoV-2 infections as study of these infections reveal unusually large numbers of nucleotide changes and deletion mutations and often high ratios of non-synonymous changes. In addition to this, convalescent plasma treatment can cause intra-patient virus genetic diversity (​11​).

What does the new mutation mean in terms of impact and epidemiology?

There was an increase in cases with the new strain in total and in

proportion to the old (​1​). What does that mean for us?

This is what the internet says:

The COVID-19 genomics UK consortium (COG) reports about a “priority set of SARS-CoV-2 Spike mutations that are of particular interest based on potential epidemiological significance in the UK and/or biological evidence based on the literature or unpublished work.” (​9​)

The New and Emerging Respiratory Virus Threats Advisory Group of the British government (NERVTAG) discussed the new variant on Friday and concluded that its growth rate is higher by 67-75% and that this is likely due to a selective advantage. “In summary, NERVTAG has moderate confidence that VUI-202012/01 demonstrates a substantial increase in transmissibility compared to other variants.” (​12​) This is very likely the source of Boris Johnson’s claim to this strain being “70% more infectious”.

The English government writes that PHE (Public Health England) „is working with partners to investigate and plans to share its findings over the next 2 weeks. There is currently no evidence to suggest that the variant has any impact on disease severity, antibody response or vaccine efficacy. High numbers of cases of the variant virus have been observed in some areas where there is also a high incidence of COVID-19. It is not yet known whether the variant is responsible for these increased numbers of cases.” (​13​)

Conclusion

From this, we conclude that the British government, and we, do not know yet. It has not been conclusively shown that the new variant is more infectious (likely), has an easier time to evade the host immune system or if the vaccine will be less effective against it (very unlikely). The epidemologic model which predicts a higher tranmissability has still to be published, the science is still in the making. Tests of vaccines against the new variant are ongoing and will take a few weeks. There is yet little evidence that this new variant poses a significantly bigger threat than others - or to the contrary.

Acknowledgements

While I am listed as author of this article, it could not have been written without the help and research by Pairoh Seeliger, Lea von Soosten, Luise Kandler, Erik Nebelung and Oliver Kippes who all helped in this.
I would also thank Nicolai Wilk from Thermo Fisher Scientific who quickly responded to my questions about their test.


The title picture shows mutation cards from the game Pandemic Expansion: On the Brink by Z-Man Games.


  1. ​*​
    The 69-70del mutation is predominantly observed in B.1.1 (including B.1.1.7), B.1.258, and the cluster 5 variant lineages of SARS-CoV-2.

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