How is SARS-CoV-2 'deactivated' for some Covid vaccines (for example Covaxin)?

How is SARS-CoV-2 'deactivated' for some Covid vaccines (for example Covaxin)?

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Some Covid vaccines like Covaxin employ a 'Whole-Virion Inactivated Vero Cell'.

How is the virion 'deactivated' for the vaccine?

For Covaxin (BBV152), SARS-CoV-2 was inactivated by treatment with β-propiolactone [1]. β-propiolactone reacts with and modifies, among other things, nucleic acids, thus preventing their replication [2].

[1] Yadav P, Ella R, Kumar S, et al. 2020. Remarkable immunogenicity and protective efficacy of BBV152, an inactivated SARS-CoV-2 vaccine in rhesus macaques. Preprint.

[2] Perrin P, Morgeaux S. 1995. Inactivation of DNA by β-propiolactone. Biologicals 23(3):207-211.

How were researchers able to develop COVID-19 vaccines so quickly?

Vaccine development is typically measured in years, not months. But as the COVID-19 pandemic rages on, scientists are racing against the clock to develop an immunization that provides protection against the SARS-CoV-2 virus. The results are breaking development records.

As challenging as developing and distributing a vaccine will be, the nation&rsquos scientific community also faces another obstacle &mdash convincing an increasingly skeptical public that the COVID-19 vaccine is safe and how important it is to get a COVID-19 vaccination in the first place.

&ldquoEven the most effective vaccine can&rsquot protect us or our loved ones if people are afraid to take it or will not take it,&rdquo said Kathleen Mullane, DO, PharmD, director of infectious disease clinical trials at UChicago Medicine. &ldquoWe know things are moving faster than ever, but the nation&rsquos scientific community has cooperated and collaborated in ways as never before and we are absolutely committed to making sure whatever is ultimately approved works and is safe. I am going to get vaccinated and am recommending vaccination for my family and friends because I believe in the safety and efficacy of these agents.&rdquo

The rapid progress on a COVID-19 vaccine means that data regarding the long-term safety and durability of these vaccines will still be flowing in long after a vaccine has been approved for emergency use. Nevertheless, those wondering about vaccine safety may be encouraged that, despite the speed in which these vaccines have been developed, the important regulatory and evaluation checkpoints designed to protect patients were followed. These milestones help to determine how safe and effective a vaccine will be, and whether or not the benefits are worth any potential risks.

Operation Warp Speed: Accelerating vaccine research

Before the COVID-19 pandemic, getting a new vaccine from concept to approval could take 10 years and billions of dollars. With only one in 10 vaccine candidates making it to market, vaccine development is a risky proposition for pharmaceutical manufacturers. For those who are unfamiliar with the methodical process of clinical research, the process can feel torturously slow. First, researchers must study the structure and infectious behavior of a pathogen. Then, they figure out how to get the human body to best produce an immune response to fight against it. Next, the vaccine is tested for safety and efficacy &mdash first using cell, animal and mathematical models, and later in multiphase human clinical trials involving thousands of participants. Only then can the federal approval process begin.

With the clock ticking on the COVID-19 pandemic, pharmaceutical companies are tapping into already established vaccine technology that could hasten the process toward producing a safe vaccine.

Dozens of vaccines against the SARS-CoV-2 virus are being developed by global pharmaceutical companies, but so far only a handful have reached large-scale, phase 3 clinical trials. In phase 3 trials, tens of thousands of volunteers participate to test the safety and effectiveness of the immunization. So far, 11 phase 3 trials have launched globally, although more are expected in the coming months and years as other research efforts move through the pipeline.

They&rsquore getting a boost from Operation Warp Speed (OWS), a collaboration between the pharmaceutical industry and the federal government. To offset the cost of the development of the COVID-19 vaccine and to help mobilize approved vaccines as quickly as possible to the American public, the government established a funding program backed by nearly $10 billion in federal funds. OWS began with an ambitious initial goal: to deliver 300 million doses of a safe and effective vaccine to Americans beginning in January 2021.

This financial investment has greatly accelerated the timeline for the development of vaccines through clinical trials, FDA review and mass distribution of a vaccine. Through the collaboration of established vaccine study networks, experienced physician scientists have significantly reduced the time and cost burden of developing clinical trials sites and enrolling volunteers to participate in these important studies. All of these factors in turn mean that once a vaccine passed critical safety and efficacy milestones and received emergency use approval (EUA) from the federal government, healthcare organizations were able to start providing the vaccine to patients in a matter of days. For example, the Pfizer/BioNTech mRNA vaccine was approved for emergency use by the FDA on Thursday, December 10, 2020 healthcare workers were being vaccinated by Monday, December 14.

Vaccine technology and clinical trials

It should also be reassuring that nearly 200 years of vaccine development has generated a number of highly effective and safe vaccine platforms, requiring less time and effort to produce new kinds of vaccines. Recycling existing vaccine technology allows researchers to focus their time on identifying the best targets that will produce the strongest immune response with the fewest side effects.

&ldquoReally, most of the vaccine platform development work is already done,&rdquo said Habibul Ahsan, MD, Director of the Institute for Population and Precision Health at the University of Chicago Medicine. &ldquoYou just have to do the remaining part, which is adding the right viral antigens to the already-proven platform and making sure it&rsquos safe and effective in humans. Even in just the last five to 10 years, we&rsquove made big leaps in developing new kinds of vaccine platforms like those being tested for SARS-CoV-2.&rdquo

Vaccines work by presenting the body&rsquos immune system with pathogen proteins, called antigens, that activate the immune response and generate antibodies to protect against the disease.

The vaccine candidates currently making headlines use mRNA and vector-based platforms. These vaccines induce the body to produce the viral antigens, which generate the appropriate immune response. Vector-based vaccines have been developed in the past for diseases including SARS, MERS, and most notably, the deadly Ebola virus, and mRNA vaccines have previously been tested to prevent the Zika virus.

These next-generation immunizations have never been tried at such a large scale before, but there is already evidence that these platforms are safe and effective, with a reduced risk of the side effects generated by live attenuated or deactivated whole-virus vaccines.

&ldquoThe mRNA and vector vaccines are a newer technology the first products were developed in 1999,&rdquo said Mullane. &ldquoBased on our understanding of human biology, there is no reason to believe that they should pose any greater risk than any of the more traditional types of vaccines. If anything, the biggest concern is how long they are effective. The preliminary efficacy data so far is extremely promising.&rdquo

To hedge against uncertainty, the FDA added additional rules to provide increased safety by having specified checkpoints for the accelerated COVID-19 trials. That includes requiring researchers to collect at least two months of follow-up data from a majority of each trial&rsquos participants, even if early data shows promising results, and long-term safety and efficacy out to two years after receipt of the vaccines.

To accelerate development, many COVID-19 trials are conducted in studies that combine phases 1, 2 and/or 3 where researchers begin by vaccinating a smaller number of healthy volunteers. As the trial continues, and if the vaccine appears to be safe, it then opens up to more participants, such as those with preexisting health conditions. Large-scale phase 3 efficacy trials ultimately include tens of thousands of volunteers. The current trial lineup includes a variety of vaccine types &mdash both tried-and-true models as well as next-generation approaches.

The speed at which these trials are progressing has raised questions about whether or not they are safe. Aware of lingering mistrust due to the politicization of the pandemic and historic medical disenfranchisement in certain communities, scientists involved in the COVID-19 vaccine research are being careful not to overstate the early results from ongoing clinical trials and be transparent about the risks involved.

Many are making efforts to get out into the community to speak with potential volunteers, address their concerns and offer an opportunity to participate, particularly in the large-scale phase 3 trials. For example, at UChicago Medicine, clinicians are taking mobile medical units into the surrounding neighborhoods to take the vaccine right to people&rsquos front doors.

&ldquoMany centers recruiting for these trials are not readily accessible by minority and low-income populations,&rdquo said Ahsan. &ldquoBut UChicago Medicine has been working hard to build strong relationships with our local community and make sure they know that we&rsquore here to serve them.&rdquo

What risks do vaccines pose?

Like most medical treatments, any vaccine is accompanied by some degree of risk. Side effects are usually mild, ranging from soreness at the site of injection to a slight fever and body aches. In one in 100,000 cases, vaccines can trigger severe allergic reactions. Even more rare (the estimate is one in a million) is an increased risk of developing autoimmune conditions that affect the nervous system, such as Guillain-Barre Syndrome.

Two separate studies where live non-replicative vector virus vaccines &mdash U.K.-based phase 3 AstraZeneca vaccine trial and U.S.-based phase 3 Janssen vaccine trial &mdash were briefly paused after a participant experienced an unexplained medical event known as an &ldquoadverse reaction&rdquo that may have been linked to their participation in the study. Both have since resumed after researchers and regulators determined that there was no clear connection between the vaccine and the medical events and deemed them safe enough to continue. No adverse events have yet been linked to the mRNA vaccine candidates, except for a handful of allergic reactions requiring EpiPens.

The challenge, particularly in the face of a global pandemic, comes down to finding the balance between the benefits of the vaccine and the risk it may pose to those who receive it. In the most situations, the balance comes down on the side of the vaccine.

&ldquoRight now, we are racing against the clock,&rdquo Ahsan said. &ldquoMaybe in six months or a year, if we haven&rsquot approved a vaccine, enough people will have gotten sick that the potential side effects are no longer worth the risk &mdash but in order to achieve that kind of herd immunity, 50 or 60 percent of the U.S. population would have to contract the virus. That&rsquos 150 or 200 million people contracting COVID-19, and probably over a million deaths. It is absolutely worthwhile to try to avoid that.&rdquo

What will it take to get &ldquoback to normal&rdquo?

Before any vaccine can receive federal approval, even for emergency use, investigators must wait until tens of thousands of volunteers receive their experimental vaccine. Then, they wait for enough time to pass for some of those volunteers to be exposed to COVID-19, which tells how effective each vaccine is. Scientists are also studying whether those who received the vaccine &mdash versus a placebo &mdash had less severe forms of illness. Without data that conclusively show vaccines are both safe and effective, they won&rsquot be approved for use in the general public.

Once a clinical trial collects enough data to show a vaccine is both safe and effective, the vaccine heads to federal regulators. The pharmaceutical company that developed the product submits data to the FDA, where it is reviewed and reanalyzed by federal statisticians and an external advisory board of scientific and medical experts. Since the COVID-19 vaccines will be submitted to the FDA before any long-term data is captured, it&rsquos likely a vaccine will receive an emergency use authorization rather than full approval. This was the case for the Pfizer/BioNTech mRNA vaccine, which was approved for emergency use by the FDA on December 10, 2020, and the Moderna mRNA vaccine, approved on December 18, 2020.

Next comes the challenge of manufacturing and distributing a vaccine, particularly in the early days when there&rsquos a limited supply. Authorities say 20 to 30 million doses could be available in January, but the full rollout may take months to get enough batches for the general public. In the interim, authorities will prioritize distribution to those most at risk of contracting COVID-19 or those who are at highest risk of suffering the most severe effects of the illness, such as health care workers, older adults, adults with pre-existing conditions and essential workers.

As a new vaccine is distributed, the clinical trials will go on and data will continue to flow in about its long-term effectiveness and any potential safety issues. This will allow researchers and healthcare providers to adapt distribution as necessary.

Realistically, the general public likely won&rsquot have access to a vaccine until sometime this summer. That&rsquos far later than Operation Warp Speed&rsquos initial goal of having 300 million doses available by January, but significantly faster than any other vaccine development effort to date.

As a vaccine is rolled out, each individual should speak with their physician about their own unique health status and whether or not a vaccine is the right choice for them, particularly those individuals who belong to groups that were not included in the clinical trials.

Ideally, the evidence will be strong enough that most Americans will feel safe receiving the vaccine. Getting enough people vaccinated with be critical for achieving herd immunity, the point at which a disease can no longer spread because enough of the community is vaccinated against or is immune to it.

In the meantime, the world is waiting breathlessly to see whether or not these vaccines prove to be the tool we need to get back on the path to normal.

Two perspectives on measuring transmission

If a Covid-19 vaccine can reduce SARS-CoV-2 infection events, asymptomatic or otherwise, this may signal that virus transmission to others could be reduced, said Bottazzi. That theory is based on the thinking that when there are fewer people infected with the virus, then there are fewer people spreading the virus, she explained.

Yet Nikolai Petrovsky, PhD, professor, College of Medicine and Public Health, Flinders University, Adelaide, Australia, differed, noting a vaccine’s ability in reducing infection is a questionable surrogate for transmission reduction. Transmission should be measured based on the nonvaccinated person who is exposed to SARS-CoV-2, and not based on the vaccinated, infected person potentially transmitting the virus, he explained. “Transmission is about the next person in the chain,” Petrovsky said, adding that infection rates and transmission rates should not be conflated.

While there may be association between infection and transmission, there is insufficient data to assess if there is a linear correlation, said Gary Kobinger, PhD, head, Vector Design and Immunotherapy Special Pathogens, Medical Microbiology, University of Manitoba, Canada. Indeed, vaccine transmission efficacy is critical to be measured in those who are not vaccinated but exposed to the virus, but there is also value in collecting data from the virus spreader, added Rory de Vries, PhD, assistant professor, Department of Viroscience, Erasmus University Medical Centre, Rotterdam, The Netherlands.

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2. Vaccine design approaches

2.1. SARS-CoV-2 antigen selection

The SARS-CoV-2 S protein binds primarily to the ACE2 receptors to mediate viral entry, in the upper and lower respiratory tracts. The mature S protein is a trimeric class I fusion protein located on the surface of the virion. It possesses two fragments, the S1 containing the receptor binding domain (RBD) and the S2 containing the fusion peptide. Different studies with monoclonal antibodies have demonstrated that infected humans develop robust neutralizing antibodies against the S protein and in particular against the S1 fragment with the receptor-binding domain (RBD) of the SARS-CoV-2 ( Baum et al., 2020 , Hansen et al., 2020 , Ju et al., 2020 ). In early studies for SARS-CoV-2 vaccines, the N protein was also evaluated for effectiveness but, using in vivo models, N-based vaccines resulted in no protection. Furthermore, they showed an exacerbation of the infection due to increased pulmonary eosinophilic infiltration ( Deming et al., 2006 ). M and E proteins are of less interest as vaccine targets due to lower immunogenicity ( Du et al., 2008 ).

2.2. Vaccine platforms

Advances in virology, molecular biology and immunology have created many alternatives to traditional vaccine approaches. More than 100 vaccine candidates against the SARS-CoV-2 virus are currently in development (“Vaccines – COVID19 Vaccine Tracker”), based on several different platforms ( Fig. 4 ). These platforms can be divided into “traditional” approaches (i.e., live attenuated or inactivated virus vaccines) and “innovative approaches” such as RNA or DNA vaccines and recombinant viral-vectored vaccines.

Vaccine platforms under development against SARS-CoV-2.

2.2.1. Live attenuated viral vaccines

Live attenuated vaccines derive directly from the pathogenic viruses that still possess the ability to infect cells and replicate but are treated in order to cause no or only very mild disease. The attenuation can be completed by growing the virus at unfavourable conditions such as at non-optimal temperature or by rational modification of the virus genome (e.g., codon de-optimization, removal of genes responsible for counteracting innate immune recognition ( Broadbent et al., 2016 , Talon et al., 2000 )). However, these techniques are time-consuming and technically challenging, resulting in a difficult and long development. Being nearly identical to the natural virus causing the infection, a live attenuated virus usually creates a strong and long-lasting humoral and cell-mediated immune response after a prime/boost vaccination regimen. Moreover, since the virus is replicating after the vaccination, the immune response is targeting both structural and non-structural viral proteins, widening the humoral and cellular immune responses without the use of adjuvants since these vaccines already contain naturally occurring adjuvants ( Lee and Nguyen, 2015 ). This type of vaccine can be given intranasally to induce a mucosal immune response such as in the case of the quadrivalent influenza vaccine against A(H1N1), A(H3N2) and two influenza B viruses available in the market with the brand name FluMist Quadrivalent (“ FluMist Quadrivalent | FDA ”). It is easily administered as 0.2 mL suspension supplied in a single-dose pre-filled intranasal spray device to be divided approximately one-half into each nostril.

2.2.2. Inactivated viral vaccines

In inactivated viral vaccines the whole disease-causing virus or a part of it (where the genetic material has been wrecked) is usually present. Compared to live attenuated viral vaccines, they are considered safer and more stable and although their genetic material has been destroyed, they still contain many antigenic proteins and hence, as in the case for coronaviruses (e.g. SARS-CoV-2), the immune responses are likely to target many different proteins such as the S but also M, E, and N. Inactivated vaccines only stimulate antibody-mediated responses, which can be weaker and less long-lived, as compared to live attenuated vaccines, and hence, inactivated vaccines are often administered alongside adjuvants and also booster doses may be required. The vaccine production requires biosafety level 3 facilities in which the virus is grown in a cell culture (usually Vero cells) followed by the inactivation. The productivity of the virus in cell culture could affect the final production yield ( Yadav et al., 2021 ). This type of vaccine has proven to be safe and effective in the prevention of diseases like polio and influenza ( - accessed March 22, 2021).

2.2.3. Recombinant viral-vectored vaccines

Viral vector-based vaccines (in the form of a modified harmless version of an alternative virus) use a modified virus (the vector) to deliver the genetic code (RNA or DNA) for an antigen, (e.g., in the case of COVID-19 the S protein) into human cells which then will produce the antigen. Infecting the cells and instructing them to produce the antigen, this type of vaccine mimic a natural viral infection in order to generate the requested immune response ( Rollier et al., 2011 ). This mechanism induces a strong cellular immune response by T cells as well the production of antibodies by B cells. The viral vectors are grown in cell lines and their production is quick and easy ( Sebastian and Lambe, 2018 ).

Viral vectors can be replicating and non-replicating. Replicating viral vectors possess the ability to replicate and thus they can produce new viral particles providing a continuous source of vaccine antigens for prolonged periods. This results in a stronger immune response with a single dose compared to the non-replicating viral vectors. Replicating viral vectors are selected so that the virus cannot cause a disease whilst infecting the host. They typically derive from attenuated viruses engineered to express the specific antigen protein such as the S protein for COVID-19 vaccine. On the other hand, non-replicating viral vectors do not retain the ability to make new viral particles because the key viral genes for the replication have been previously removed. The most common approaches of this vaccine type are based on an adenovirus delivered intramuscularly. As an advantage of viral vectored vaccines, their production does not require the use of live pathogen viruses, the vectors can be easily produced in large quantities showing a good stimulation of both B and T cell responses in vivo ( Zhu et al., 2020a ). As a disadvantage, pre-existing vector immunity can neutralize the vaccine efficacy. However, this problem can be easily avoided by using vectors that are rare in humans ( Mercado et al., 2020 ), derived from animals ( Folegatti et al., 2020 ) or viruses that do not generate much immunity. Moreover, as vector immunity can be problematic during the second dose in a prime-boost regimen, the use of two different viral vectors during the two doses can help avoiding this problem. Nevertheless, in this case, vaccine antigen can only be produced as long as the initial vaccine remains in infected cells, resulting in a generally weaker immune response. Booster doses are likely to be required.

An example of a viral vector vaccine is the recombinant, replication-competent rVSV-ZEBOV vaccine against Ebola ( Marzi et al., 2011 ) approved by FDA in 2019. It consists of vesicular stomatitis virus (VSV) genetically modified to express the main glycoprotein from the Zaire ebolavirus. It is a suspension administered intramuscularly with a single dose ( - accessed March 22, 2021).

2.2.4. Protein subunit vaccines

Protein subunit vaccines (also called acellular vaccines) do not contain any whole virus, but instead purified antigenic fragments such as isolated proteins (e.g., the S protein on the SARS-CoV-2 virus) specifically selected because of their capacity to stimulate the immune system.

Many different antigens can be selected to develop acellular vaccines such as specific isolated proteins from viral or bacterial pathogens, chains of sugar molecules (polysaccharides) found in the cell walls of some bacteria or a carrier protein binding a polysaccharide chain in order to boost the immune response. Acellular vaccines are generally considered very safe since they cannot cause the disease. The immune response usually is not as robust as for live attenuated vaccines, hence, booster doses are most often required. A possible disadvantage of this type of vaccine is that isolated proteins could be denatured and thus bind to different antibodies than the protein of the pathogen. In the case of SARS-CoV-2, the antigenic proteins used are the S protein or the RBD. The advantage of this type of vaccine is that live virus is not handled. Commonly used protein subunit vaccines are the acellular pertussis (aP) vaccines that contain the inactivated pertussis toxin detoxified either by treatment with a chemical or by using molecular genetic techniques ( - accessed March 22, 2021). To improve the efficacy of this vaccine, alum is added as adjuvant to promote a stronger antibody response. ( Allen and Mills, 2014 ). Another acellular vaccine is against Hepatitis B containing the hepatitis B virus surface antigen (HBsAg) produced with recombinant technology. Even this vaccine contains aluminium phosphate or aluminium hydroxide as adjuvant to boost the immune response after the administration ( - accessed March 22, 2021).

2.2.5. RNA and DNA vaccines

Nucleic acid-based vaccines follow a different strategy compared to the other vaccines. Instead of directly providing the protein antigen to the body, they deliver the genetic code of the antigen to the cells in the body instructing the cells to produce the antigen that then will stimulate an immune response. This type of vaccines is quick and easy to develop and are the most promising vaccines for the future. They are divided into RNA- and DNA-based vaccines. RNA vaccines use messenger RNA (mRNA) or self-replicating RNA normally formulated in a particulate carrier such as a lipidic bilayer membrane (liposome). This formulation protects the mRNA when it first enters the body and helps cell internalization ( Pardi et al., 2015 ). Higher doses are required for mRNA than for self-replicating RNA, which amplifies itself. When the mRNA is inside the cells, it can be translated into the antigen protein by ribosomes to start the stimulation of the immune response. Then the mRNA is naturally broken down and removed by the body. A main advantage of this technology is that the vaccine can be produced completely without the use of cell cultures, however, the long-term storage stability is challenging since it requires frozen storage. RNA-based vaccines are usually administered by injection and are therefore unlikely to induce strong mucosal immunity ( Pardi et al., 2018 ).

Being more stable than mRNA/RNA, DNA do not require to be formulated in particulate carriers. They are based on plasmid DNA that can be produced at large scale in bacteria. The DNA contains mammalian expression promoters and the specific gene that encodes for the antigen (e.g., the spike protein) produced after the uptake in the cells of the vaccinated person. To be delivered, they usually need delivery strategies such as electroporation that help the DNA cellular uptake. Both these technologies based on nucleic acids are the latest frontier of vaccination and up till now two different mRNA vaccines have been approved for human use (i.e., Moderna and Pfizer/BioNTech ( Baden et al., 2021 , Polack et al., 2020 )) meanwhile the most advanced DNA vaccine so far is the INO-4800 from Inovio that has entered Phase 2/3 clinical trials (“Safety, Immunogenicity, and Efficacy of INO-4800 for COVID-19 in Healthy Seronegative Adults at High Risk of SARS-CoV-2 Exposure - Full Text View -”).

2.3. Adjuvants

Many vaccine formulations contain an adjuvant or adjuvants combinations that enhance the immune response to the vaccination. The word �juvant” means “to help/aid”, and initially adjuvants were used only to increase the immunogenic potential of purified antigens. Not all the types of vaccines need an adjuvant such as the live attenuated virus that possess naturally occurring adjuvants. In recent years, by knowing and understanding the immunology of vaccination, the role of adjuvants has expanded ( Pasquale et al., 2015 ).

The first adjuvants authorized (nearly 70 years ago) for human use were aluminium salts (e.g., aluminium hydroxide, aluminium phosphate, aluminium potassium sulphate (alum)). They are still the most widely used because of their wide-spectrum ability to strengthen immune responses and their safety. They act primarily to increase antibody production with an immune mechanism that remains incompletely understood ( Lee and Nguyen, 2015 ).

Newer adjuvants have been developed to target specific components of the body’s immune response such as the tall-like receptors (TLR) that, when triggered, stimulate the production of pro-inflammatory cytokines/chemokines and type I interferons that increase the host’s ability to eliminate the pathogen. Adaptive immunity is developed immediately after the innate immune response so that the protection against disease is stronger and lasts longer ( Steinhagen et al., 2011 ).

Among new adjuvants already licensed, AS04 ( Didierlaurent et al., 2009 ) is a mixture of monophosphoryl lipid A that act as TLR4 agonist and aluminium salt, MF59 ( Liang et al., 2020 ) is an oil in water emulsion composed of squalene that act by improving antigen uptake, recruiting immune cells and promoting the migration of activated APS, AS01B ( Alving et al., 2012 ) is a liposomal combination of monophosphoryl lipid A and a natural compound extracted from the Chilean soapbark tree (i.e., QS-21), and Cytosine phosphoguanine (CpG) ( Liang et al., 2020 ) that is a synthetic form of DNA that mimics bacterial and viral genetic material acting as TLR9 agonist. Different examples of vaccines that uses adjuvants are reported in Fig. 5 .

Timeline of the main adjuvants used in human vaccines.

Are the vaccines safe?

Every vaccine that is approved in the United States, even if under emergency use authorization, undergoes stringent safety testing, and the CDC continues to collect data on any side effects or adverse outcomes that could be related to the vaccine over time.

People who receive vaccines may experience a number of side effects, such as a sore arm, fever, fatigue, chills, nausea, and body aches — especially after the second dose of one of the two-dose regimens. This is a sign that the immune system is reacting and is not a cause for concern. The CDC recommends taking a painkiller after (not before) getting the shot and exercising the arm to avoid soreness.

The side effects are generally more intense after the second shot, as the immune system reacts to the known spike protein. The CDC also reports that 80% of those who reported experiencing side effects were women, which may be related to sex hormones’ role in the immune response, according to a New York Times article.

There are some rare serious side effects, such as anaphylaxis — a life-threatening, but treatable, allergic reaction. In the United States, this reaction has occurred in about two to five people per million vaccinated and has not resulted in any deaths.

The CDC requires that vaccinated people stay at the vaccination site for observation for at least 15 minutes after getting the shot in case they do have a negative reaction.

Kathryn Edwards, MD, a vaccinologist and the Sarah H. Sell and Cornelius Vanderbilt professor of pediatrics in the Division of Infectious Diseases at Vanderbilt University School of Medicine in Nashville, Tennessee, spends most of her day assessing reactions after COVID-19 vaccines as part of her CDC-funded Clinical Immunization Safety Assessment unit. Her team, which is working with allergists, believes that someone who has an immediate anaphylactic reaction to the first dose of an mRNA vaccine should not receive the second dose of that vaccine but rather may be able to get the Johnson & Johnson vaccine for their second shot with careful monitoring.

“I’ve been doing this a long time, and I don’t know that I’ve worked any harder than I am now. We want to make sure that the public knows that we want these vaccines to be both safe and effective.”

Kathryn Edwards, MD
Vaccinologist and professor of pediatrics in the Division of Infectious Diseases at Vanderbilt University School of Medicine

Edwards also cautions that not all adverse reactions that happen around the time of vaccination are caused by the vaccine. As people with underlying conditions — particularly older individuals — receive a vaccine, heart attacks or strokes will happen and could be coincidental. Her team is working to determine whether certain reactions are happening more often than would be expected after vaccination.

For example, there is a concern that came up with the AstraZeneca vaccine that resulted in several countries pausing or limiting its use due to reports of blood clots. Edwards says that the number of people who have experienced blood clots after being vaccinated in the United States so far is lower than what would be expected in the everyday population. Still, the CDC is continually looking at these rates to identify any signal for a reaction that might be associated with a vaccine.

Though any long-term effects of the vaccines are not yet known, Edwards says that she and the CDC are being vigilant in investigating any potential problems as they arise.

“I’ve been doing this a long time,” she notes. “And I don’t know that I’ve worked any harder than I am now. We want to make sure that the public knows that we want these vaccines to be both safe and effective.”

Here’s what makes 4 promising COVID-19 vaccines unique — and potentially useful

Millions of people, like Reinaldo de Souza Santos of the Baré ethnic group in Brazil (shown getting the Sinovac vaccine), are getting COVID-19 vaccine shots, but more vaccines are needed. Some upcoming vaccines may help fill the gap.

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Barely a year after the World Health Organization declared the coronavirus outbreak a pandemic, 11 vaccines worldwide have been granted emergency use authorization or given full approval. Millions of shots are going into arms every day: As of March 19, 410 million people around the world have gotten the jabs.

As mind-boggling as that is, it still falls far short of the need.

Those 11 vaccines “will not be enough to fulfill the global need in the short term,” says Esther Krofah, executive director of FasterCures, part of the Milken Institute think tank in Washington, D.C. Of the more than 7 billion people on Earth, only about 1.2 percent of the world’s population is now fully vaccinated against the coronavirus. “We need as many vaccines over the finish line as can get through the scientific process,” she says.

Help may be on the way. Another 251 COVID-19 vaccines are at some stage of development with 60 far enough along to be tested in people, says Carly Gasca, senior associate at FasterCures.

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Some vaccines are close to the finish line. For example, one made by Novavax of Gaithersburg, Md., may soon request emergency use authorization in the United States and other countries. But vaccines in the pipeline can fail at any stage. Already at least four vaccine candidates have been abandoned, including two from pharmaceutical giant Merck that failed to generate immune responses as strong as those from natural infections. That company is now helping produce Johnson & Johnson’s one-dose vaccine (SN: 2/27/21).

Among the hurdles: The already-in-use vaccines have set a high bar. For instance, mRNA vaccines from Moderna and Pfizer have proven to have about 94 to 95 percent efficacy in clinical trials and in real-world situations and may protect against infection and disease after just one shot (SN: 2/26/21). And finding people willing to participate in gold-standard clinical trials in which they might get a placebo instead of a vaccine could be tough, especially in countries where other authorized vaccines are available.

“You have to have something super über-duper special about your product to survive in this environment,” says Onyema Ogbuagu, a virologist who heads COVID-19 clinical trials at Yale School of Medicine.

That edge could come from logistics. To be effective, vaccines have to get into people’s bodies. So unlike the Pfizer and Moderna shots, vaccines that don’t have to be frozen have a better chance of being used in rural or remote areas and places that don’t have resources to buy and maintain freezers, Gasca says.

Or an edge could come from an ability to handle emerging variants of the coronavirus that may be more infectious, more deadly or both (SN: 2/5/21). “The variants emerging are changing the landscape of the kind of virus we’re fighting now versus the virus that we were fighting in the fall and in the summer,” Krofah says. New vaccines may need to combat even more variants.

Here’s a closer look at some of the novel ways vaccine makers are approaching these challenges.


How it works: COVAXX designed small pieces of protein, called peptides, from several of the proteins from SARS-CoV-2, the coronavirus that causes COVID-19. Peptides mimic important structures within the coronavirus proteins, including a part of the spike protein used to break into cells. When injected into the body, the lab-made peptides prod the immune system to build antibodies and gear up other immune cells to attack the coronavirus should the vaccinated person encounter it later. (The Dallas-based company is not connected to the similarly named World Health Organization’s COVAX program that distributes vaccines to low-income countries.)

How it’s different: While other vaccines, including Novavax’s candidate, use the entire spike protein, COVAXX has homed in on portions of coronavirus proteins that are important for function and are likely to provoke a reaction from the immune system. The vaccine is stable at refrigerator temperature.

Clinical trial status: The company completed Phase I testing for safety and the ability to rev up the immune system in 60 adults. All of the volunteers made antibodies and had immune cells known as T cells and B cells trained to recognize the coronavirus in the event of future encounters. Participants had only mild side effects, with few people reporting symptoms such as fever and fatigue.

Researchers at a COVAXX facility on Long Island, New York, are helping devise and test a vaccine made of peptides, small portions of proteins, from the coronavirus. COVAXX

COVAXX is doing Phase II testing in Taiwan to learn more about the immune response and side effects. Phase II and III testing will begin soon in Brazil to determine the vaccine’s efficacy.

Combating variants: The company is already working a second generation of the vaccine that could work against multiple variants, says COVAXX cofounder Mei Mei Hu.

Thoughts on being behind: “I never thought this was winner takes all,” Hu says. “The demand is still incredible, and even when it is met, there will continue to be unmet needs,” including vaccines that can tackle variants, vaccines that work well for people with suppressed immune systems, vaccines for children and vaccines that can mix and match with others in case booster shots are needed.


How it works: The San Francisco–based company engineered a common cold virus called an adenovirus to carry instructions for making two coronavirus proteins into human cells. There, the proteins can be made to prime the immune system to later fend off the coronavirus.

How it’s different: Vaxart’s vaccine is a pill: It can be swallowed instead of injected. The tablets can be stored at room temperature and don’t need trained medical workers or equipment to administer. That could make the pill ideal for sending booster doses through the mail or using in hard-to-reach places where keeping vaccines cold is difficult. And people who are afraid of needles might like a tablet alternative.

Taking the vaccine orally also may produce more of an immune response in the mucous membranes that line the nose, mouth, throat and digestive tract than injected vaccines do, says Sean Tucker, Vaxart’s founder and chief scientific officer.

Other vaccines already in use, including the Johnson & Johnson, AstraZeneca, Sputnik V and CanSino vaccines, also contain engineered adenoviruses. But those vaccines have instructions for making just one coronavirus protein, the famous spike protein. Vaxart’s vaccine contains instructions for making the spike protein, and also for the nucleocapsid, or N protein. The N protein is important for replication and assembly of the coronavirus. It provides another target for antibodies that can shut the virus down.

A new COVID-19 vaccine in pill form (shown) might provide easy ways to get inoculations and boosters to people even in hard-to-reach places. Vaxart Inc.

Clinical trial status: Because the vaccine works in airways and the digestive tract, it is difficult to directly compare with injected vaccines, Tucker says. But the vaccine appears to generate antibodies against both the spike and N proteins and revs up T cells to combat the virus, according to preliminary results from a small Phase I trial to test safety and immune responses. Full results are expected soon.

Side effects were generally mild. Some who took a high dose experienced diarrhea and nausea. Those symptoms are not usually seen with injected vaccines. A lower dose of the tablet vaccine didn’t produce those symptoms.

The company will soon begin a Phase IIa study to determine the optimal dose of the vaccine, and Tucker says the team hopes to start an efficacy study later this year.

Combating variants: Even though the spike protein has undergone many changes, the N protein hasn’t altered much. The difference between the N proteins in the B.1.351 variant first described in South Africa and the original SARS-CoV-2 is just one amino acid. Hopefully that will mean antibodies and T cells against the N protein can neutralize variants as well as they do the original virus, Tucker says. Meanwhile, he says, “we are looking at new versions of the vaccines in research and will test preclinically [in animals or cells] to see if there are advantages to making new matched vaccines.”

Thoughts on being behind: The coronavirus may never go away entirely. If it behaves like coronaviruses that cause the common cold, people may get reinfected every two to five years. “I think our vaccine could be a great second-generation solution,” Tucker says. The pill vaccine might be an easy way to deliver boosters to people who have gotten other COVID-19 vaccines, he says.


How it works: Valneva’s vaccine is an inactivated, or “killed,” version of SARS-CoV-2. The virus used in the vaccine was isolated from a patient in Italy. The vaccine virus is grown in monkey cells and then chemically inactivated and mixed with two adjuvants, substances that enhance the body’s immune response.

Although inactivated vaccines have been used for decades, “our vaccine is not any less modern than any of the others,” says Thomas Lingelbach, the Saint-Herblain, France-based company’s president and chief executive officer.

How it’s different: It uses two adjuvants, including one made by Dynavax and used in an FDA-approved hepatitis B vaccine. Several inactivated COVID-19 vaccines, including ones made by the Chinese companies Sinopharm and Sinovac and by Bharat Biotech in India, are in use around the world. But those vaccines don’t have the extra boosts from the dual adjuvants in Valneva’s vaccine.

Clinical trial status: Results from a Phase I/II study are expected in April.

Combating variants: Because the vaccine contains the whole virus (minus one protein), variants that have tweaks in their spike protein may not be as big a problem for Valneva’s vaccines as for other vaccines. There are a lot of other parts of the virus for the immune system to recognize. The company is also working on creating versions of the vaccine based on strains circulating in people.

See all our coverage of the coronavirus outbreak

Thoughts on being behind: “We’re not entirely unhappy to be a bit slower,” Lingelbach says. The company may be able to build on other vaccines’ successes and learn from their failures. By comparing immune responses from its vaccine with already established vaccines, the company may be able to get hints of its vaccine’s efficacy early on in its development rather than having to wait for a Phase III trial. Regulators eventually may allow head-to-head comparisons of efficacy — as is commonly done with new flu vaccines — rather than testing each vaccine against a placebo.


How it works: DNA instructions for building the coronavirus spike protein are zapped into the skin with a split-second pulse of electricity. From there, cells in the body produce the spike protein and cue the immune defenses.

How it’s different: No other vaccine has this delivery method. Electrical pulses that push the DNA into cells are made by a handheld device that resembles an electric toothbrush. Some people report that the zap is less painful than a needle stick.

The vaccine may produce fewer side effects than some already in use. “We haven’t seen fatigue and fever and other systemic effects,” says Joseph Kim, INOVIO’s chief executive officer. Kim speculates it may be because the vaccine contains only DNA and saline, or because different types of cells may take up the DNA than are affected by injected vaccines. Only five of 40 people tested in a Phase I study reported any side effects, and all of those were mild, researchers reported December 23 in EClinicalMedicine.

Additionally, the vaccine can be stored for a year at room temperature and for five years in a refrigerator.

Instead of needles, INOVIO will use its Cellectra device (shown) to zap its DNA vaccine into people’s arms with a split-second pulse of electricity. INOVIO

Clinical trial status: Results from the Phase I study indicate that people make antibodies against the coronavirus at higher levels, on average, than those given the Johnson & Johnson and Sinovac vaccines, which use adenoviruses to deliver DNA instructions for building the spike protein to human cells, Kim says. It’s unclear why. And while antibody levels were lower than those produced by the mRNA vaccines, the DNA vaccine does a good job of revving up T cells to fight the coronavirus.

INOVIO has started Phase II testing of its vaccine, with early results expected soon. A Phase III trial will start once the U.S. Food and Drug Administration clears a commercial version of the DNA delivery device to be used in the trial.

Combating variants: The company is testing whether antibodies made against the vaccine can still fight off the variants. In addition, INOVIO, headquartered in Plymouth Meeting, Pa., hopes to engineer a universal COVID vaccine that could fight off known and unknown versions of SARS-CoV-2.

Thoughts on being behind: The company isn’t worried about standing out against other vaccines, Kim says. “We have several advantages as a vaccine,” he says. “We are extremely motivated to get to our efficacy trial.… We’re working very eagerly and passionately to make sure that INO-4800 is one of the arsenals that global health will have to fight this infection around the world.

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Editor's Note:

This story was updated March 31, 2021, to correct the description of how the Valneva vaccine was created and what makes it different from other vaccines. The virus used in the vaccine is doused with chemicals, not genetically engineered, to inactivate it, and its adjuvants differ.

A version of this article appears in the April 24, 2021 issue of Science News.

Coronavirus: A map of Sars-CoV-2 activated proteins

Representation of the predicted SARS-CoV-2/Human interactome [26] (available for download at, containing 200 unique interactions among 125 proteins (nodes). SARS-CoV-2 proteins are depicted as green circles, while human proteins are represented as squares. The color of human protein nodes reflects the integrated effect of MERS and SARS infections on the node network (see Supplementary Table S2) as a Normalized Enrichment Score (NES). Network visualization was performed via Cytoscape [49]. Credit: Courtesy of Journal of Clinical Medicine

What happens when the pathogen responsible for the Covid-19 pandemic, the coronavirus Sars-CoV-2, makes contact with a human bronchial cell? A group of researchers from the Universities of Bologna and Catanzaro (Italy) mapped the interactions between the virus proteins and those of humans, showing which proteins are being "activated" and "de-activated" by Sars-CoV-2.

"Gaining knowledge about the molecular effects of Sars-CoV-2 on human proteins is fundamental to devise effective drug therapies," says Federico M. Giorgi, principal investigator of the study and a researcher at the University of Bologna. "Inhibiting the interactions that we mapped may represent an effective strategy for a therapy able to contain the disruptive force of Sars-CoV-2 and other coronaviruses on human cells."

This study was published on the Journal of Clinical Medicine. The researchers were able to identify human cell defense mechanisms, when the virus enters the body, for example, as well as how Sars-CoV-2 spreads in the human body, e.g., via proteins favoring its replication.

An integrated approach

Beta-coronaviruses, a sub-family of coronaviruses, mainly cause respiratory and intestinal diseases. To date, we are aware of seven strains of beta-coronavirus that affect humans. Three of them are particularly dangerous: Sars-CoV, causing Sars, Mers-CoV, causing Mers, and the new Sars-CoV-2, causing Covid-19, the illness that has already infected over 1 million people around the globe.

We know that Sars-CoV-2 has a lot in common with its beta-coronavirus "cousins," and with Sars-CoV in particular. Nevertheless, a detailed description of how this virus attacks human cells is still missing. To shed some light on this issue, researchers compared the interactome (the set of interactions between proteins) deriving from the encounter between Sars-CoV-2 and a human cell with the available information on the behavior of Sars-CoV and Mers-CoV viruses.

"This integrated approach draws from our knowledge of other beta-coronaviruses and from what we have learned about this new coronavirus so far. Crucially, it allowed to identify the main factors behind the action of Sars-Cov-2," explains Giorgi. "As a result, we were able to create a map showing which proteins are activated, thus increasing their production, and which are deactivated, consequently decreasing their quantity, when the virus attacks a cell of the human breathing system."

This analysis revealed proteins that play a relevant role when the new coronavirus encounters a human cell. One of these proteins (MCL1) regulates the process of apoptosis (programmed cell death), an anti-viral defense mechanism, setting in motion a series of reactions that eventually cause cells to trigger their own death in order to stop the attack of the virus. Other proteins are instead limited in their scope once they come into contact with the coronavirus. The deactivation of protein EEF1A1, for example, hinders the replicating ability of the virus.

The downside, however, is that Sars-CoV-2 also exploits other mechanisms in order to spread throughout the body. Indeed, researchers came to three main conclusions. Firstly, they found out that the virus is able to hinder the activity of mitochondria (the organelles in charge of cell respiration) secondly, they discovered that some specific viral proteins (NSP7 and NSP13) are able to deactivate some cell defense mechanisms and thirdly, they observed the increase of some proteins that favur RNA metabolism, and as a consequence, the action and replication of the virus (whose genome is a single RNA strand).

Then the protein ACE2 interacts with the "spikes" of the coronavirus, allowing it to enter the cells. The analysis shows that the cells fight the virus attack, decreasing the presence of ACE2. Researchers also observed that a lower presence of this protein may damage lung tissues, thus favoring the spread of the virus anyway.

"This valuable information about the effects of the new coronavirus on the proteins of human cells may prove to be fundamental in redirecting the development of drug therapies, since common antiviral treatments seem to be unsuccessful," says Federico M. Giorgi. "Recent advances in pharmaceutical science allow for the quick development of new molecules, which may prove to be very effective to counteract the action of the virus proteins and to improve the response of human cells."

Finally, the researchers analyzed the presence of ACE2 to shed some light on the animal origin of the Sars-CoV-2 coronavirus, which was initially ascribed to bats and then also to pangolins. This study brought to the fore a closer similarity between ACE2 proteins of human cells and those of pangolins. This result supports the hypothesis that this small mammal might have been the first host of Sars-CoV-2, or at least an intermediate one between bats and humans.

The title of the study is "Master Regulator Analysis of the SARS-CoV-2/Human Interactome." The researchers are Federico M. Giorgi, Daniele Mercatelli and Carmine Ceraolo from the Department of Pharmacy and Biotechnology of the University of Bologna and Pietro H. Guzzi from the Magna Græcia University of Catanzaro.

Coronavirus Jumped From Bats To Humans With Little Genetic Change

London: The progenitor of the novel coronavirus underwent “very little change” to adapt to humans from bats, according to a new study which suggests that the ability of the virus to spread from one person to another likely evolved in the flying mammal prior to it jumping to its new human host.

The study, published in the journal PLOS Biology, assessed hundreds of thousands of sequenced genomes of the SARS-CoV-2 virus and found that for the first 11 months of the COVID-19 pandemic, there has been very little ‘important genetic change’ observed in the coronavirus.

However, it noted that some changes such as the D614G mutation, and similar tweaks in the virus spike protein has affected its biology.

“This does not mean no changes have occurred, mutations of no evolutionary significance accumulate and ‘surf’ along the millions of transmission events, like they do in all viruses,” explained study first author Oscar MacLean from the University of Glasgow’s centre for virus research in Scotland.

But the scientists said it was “surprising” how transmissible SARS-CoV-2 has been from the outset.

“Usually viruses that jump to a new host species take some time to acquire adaptations to be as capable as SARS-CoV-2 at spreading, and most never make it past that stage, resulting in dead-end spillovers or localised outbreaks,” said Sergei Pond, another co-author of the study from Temple University in the US.

Analysing the mutations undergone by the novel coronavirus and related sarbecoviruses ‒ the group of viruses the COVID virus belongs to from bats and pangolins ‒ the scientists found evidence of fairly significant change, but all before the emergence of SARS-CoV-2 in humans.

Based on this observation, the researchers said SARS-CoV-2 came with a ready-made ability to infect humans and other mammals, with these properties likely evolving in bats prior to it jumping to humans.

“While an undiscovered ‘facilitating’ intermediate species cannot be discounted, collectively, our results support the progenitor of SARS-CoV-2 being capable of efficient human transmission as a consequence of its adaptive evolutionary history in bats, not humans, which created a relatively generalist virus,” the scientists wrote in the study.

Although the novel coronavirus is still cleared by the human immune response in the vast majority of infections, the scientists cautioned that it is now moving away faster from the January 2020 variant used in all of the current vaccines to raise protective immunity.

The current vaccines will continue to work against most of the circulating variants, but as more time passes, and the bigger the differential between vaccinated and not-vaccinated numbers of people, they said there will be more opportunity for the virus to escape vaccines.

“The first race was to develop a vaccine. The race now is to get the global population vaccinated as quickly as possible,” said David L Robertson, lead author of the study from the the University of Glasgow.

Vector vaccine

Vaccines that use this: Johnson & Johnson, AstraZeneca (not yet available in the U.S.)

How it works: Vector vaccines are made from a modified version of a live virus, says Dr. Lee. Those harmless viruses&mdashin this case, an adenovirus, which is a version of the common cold&mdashare sent into your body containing an instruction manual that tells your cells to make a spike protein a harmless piece of the SARS-CoV-2 virus (that&rsquos the one that causes Covid-19). Vector vaccines will not give you Covid-19. Your body starts to make antibodies to this so that if the real spike protein comes around on the Covid-19-causing coronavirus, the antibodies will attack it and ultimately help defend your body. If you&rsquove had an MMR (measles, mumps, and rubella) or chicken pox vaccine, these work in a similar manner.

Why the Study Claiming SARS-CoV-2’s RNA Is Fused Into Human DNA Is Flawed

In September 1957, Francis Crick proposed the ‘central dogma of molecular biology’. He suggested that information always flows in living beings from DNA – a stable, inheritable molecule – through a relatively unstable intermediate, the messenger RNA, and then onto proteins, which are the workhorses of all life functions. And everywhere scientists looked, they realised all organisms followed this dogma – until 1970.

In this year, Howard Temin and David Baltimore found something odd in one group of viruses.

Viruses, like other living beings, come in all shapes and sizes, and are classified into different families. However, viruses are not classified the same way as other life forms. This is because they can be both alive and not alive – a feature that demands that taxonomists also consider other attributes that make viruses different.

Another such feature is their genetic material.

Viruses are the only known life-forms that can use RNA as their genetic material. There are different kinds of RNA-containing viruses. To propagate itself, each virus makes a copy of the information in its genetic material to pass onto its ‘daughter’ viruses. Some viruses contain the machinery to make copies of their RNA, and they don’t have a DNA component in their life cycle whatsoever. The influenza, hepatitis C and SARS-CoV-2 viruses are in this category. These viruses also deviate from the central dogma only slightly: there is no DNA, but the information flows only from the RNA to proteins.

But what Temin and Baltimore discovered in 1970 was a proper exception to the central dogma. They found viruses that could make a DNA copy with their RNA using an enzyme called reverse transcriptase, in a process called reverse transcription. A virus then mixes this DNA with the DNA of its host, thus becoming part of the host forever. Such viruses – called retroviruses – violate the central dogma because information first flows from RNA to DNA, and then from the DNA to the RNA to proteins.

Viruses like HIV and Rous sarcoma belong to this family.

In all, there are seven families, or groups, of viruses, and each group specifies special adaptations, refined over years of evolution, often through several hosts. It’s also unusual – maybe even impossible – to have members of one class of viruses show fundamental properties associated with another.

This is why a preprint paper uploaded to the bioRxiv preprint server on December 13 caught the scientific community by surprise. The paper claimed, outlandishly, that parts of the SARS-CoV-2 viral RNA could be reverse transcribed into DNA and integrated into the human genome.

According to the paper’s authors, they were attempting to explain why some COVID-19 patients showed signs of the virus in RT-PCR tests even weeks after recovering from the disease. Their explanation is based on a group of genetic entities called long interspersed nuclear elements (LINE). The human genome has multiple LINEs – effectively, parts of our DNA responsible for reverse-transcribing human RNA into DNA, and integrating it into the human DNA at a different part. The paper claims these LINEs do the same thing with parts of the novel coronavirus’s RNA as well.

This process differs from what retroviruses like HIV do routinely: they use their own proteins to convert and mix the DNA.

The authors’ claims are based largely on one primary observation and one experiment. The observation banks on a powerful tool called RNA-seq, which provides the sequences of all the RNA molecules produced by a cell. So a RNA-seq’s output is a sort of measure of all the genes that are active in the target cell. The authors reported that in cells infected with SARS-CoV-2, there were some viral RNA sequences interspersed between RNA sequences of human genes.

This data may seem convincing at first glance, but the devil is in the details. The authors appear to have overlooked the fact that in the process of preparing a sample for RNA-seq, the scientist must herself artificially reverse transcribe RNA into DNA – because only DNA can be sequenced (for further study). So the chimeric viral and human RNA could just be an artefact of the RNA-seq process, since reverse transcriptases are known to mix and match target sequences.

To prove their claims in an experimental setup, the authors genetically altered cells to make proteins that can perform reverse transcription. Then they infected these cells with the SARS-CoV-2 virus, and reported that the SARS-CoV-2 viral RNA is converted into DNA.

They performed the experiment by forcing cells to make unnatural quantities of two proteins: LINEs and HIV reverse transcriptase (RT). The problem with the former is that LINEs are rarely produced naturally in the same quantities as those in the experiment, raising doubts about whether the results reflect what is realistically possible. And the problem with the latter is that there is no chance HIV RT is naturally present in a cell infected with SARS-CoV-2 because the two viruses do not infect the same cell types. So the experimental evidence has some big loopholes that don’t in any way justify what the authors claim.

Instead, the authors could have provided data from an older technique: the Southern blot. In 1973, the English molecular biologist Edwin Southern reported a very simple way to check if a particular fragment of DNA is present in a given sample. A DNA molecule has two strands (the ‘double helix’), and the string of nucleobases on one strand can only pair to a specific string of nucleobases on the other. So Southern figured that by studying one strand, researchers could know what the other strand looked like.

The way to do this – for example – is to synthesise one strand of the SARS-CoV-2 DNA and mix it with copies of human DNA, and check for signs of binding.

The preprint paper’s lack of convincing evidence has opened it up to criticism from scientists for its erroneous assertions and unproven claims. At the same time, David Baltimore, who won a Nobel Prize for helping discover the reverse transcriptase enzyme, told the prominent Science magazine the study was “impressive”, and other news outlets have amplified his comments.

Such words have elevated the study’s profile in a way it didn’t deserve to be in the middle of a pandemic scarred by misinformation and pseudoscience. The manuscript’s bioRxiv page itself includes numerous demands from researchers around the world (as comments) to take it down.

To be clear, what the preprint’s authors have claimed is still within the realm of possibility, but their experiments and interpretations aren’t convincing. The claim is extraordinary: the first report of reverse transcription by a non-retrovirus. It would mean there’s a chance that your body keeps a record of all RNA viruses that ever infected it, and open up a whole new angle to immune memory. But extraordinary claims require extraordinary evidence – which the preprint paper doesn’t have. So for now, we wait for proof.

Arun Panchapakesan is a molecular biologist working in the HIV-AIDS laboratory at the Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru.

Watch the video: Στέλιος Χατζηπαναγιώτου. Εμβόλια για COVID-19 και Προληπτικός Εμβολιασμός για Συννοσηρότητες (July 2022).


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