Health Bulletin-April 2021

COVID VACCINES- A Brief Update

Dr Sujeeth R. Punnam, MD, FACC, Stockton, CA
Chair, Heath Committee, ATA

INTRODUCTION

An obscure viral illness SARS-CoV-2 that had its origin in the Chinese city of Wuhan has brought us into a unique crisis. Humankind lost more than 300 million people in its existence from pandemics and the most severe in recent history was the 1918 influenza pandemic. An estimated 50 million died worldwide at that time. Corona viruses are a group of viruses that usually cause disease in humans and birds. In humans, the viruses cause respiratory infections which are typically mild, and include the common cold; however, rarer forms such as SARS, MERS and the novel coronavirus causing the current outbreak can be lethal. <

Herd Immunity

When enough of the population is resistant to a germ, develop antibodies and its spread stops naturally because not enough people are able to transmit it. That means, the “herd” is immune, even though many individuals within it still are not. Vaccines create herd immunity too. That’s how diseases like smallpox were eradicated and why polio is close to being erased.  The point at which we reach herd immunity is related to the germ’s propensity to spread, expressed as its REPRODUCTION NUMBER, or R0 (pronounced R Naught). The R0 for the coronavirus is around 2.6, meaning each infected person passes it to an average of 2.6 other people, if you don’t contain. So, about 60-65% of world population should get COVID-19 disease or vaccination to contain the current pandemic.

Recovery from a viral disease rests on the combined action of antibodies that neutralize the viral particles and the killer activity of lymphocytes that track down and kill virus-infected cells. However, there are viral diseases whose healing depends mainly, if not exclusively, on the antibody response and others where the destructive action of the killer lymphocytes is fundamental.

SARS-CoV-2 Virus

It is an oily spherical particle containing a single-stranded RNA wrapped and coiled by the nucleocapsid protein. The virus outer shell consists of three other structural glycoproteins: Spike, Envelope, and Membrane, and a lipid coating.  Within a few weeks after SARS-CoV-2 virus was identified, the genome was identified and was shared across the network of world scientists. We can call it a miracle that, just eleven months after the identification of the genome, there are over 150 official vaccine projects now.

These anti-SARS-CoV-2 candidate vaccines are targeting the whole SARS-CoV-2, molecules or fragments of molecules expressed on this virus surface. These different candidate vaccines can be grouped based on the modality they are using to elicit a protective immune response.

1) LIVE ATTENUATED VACCINES
This is the most traditional technology exploited in the constitution of vaccines. Live attenuated vaccines can be obtained by growing the virus in unfavorable conditions or by generating a genetically weakened version of the virus. However, the attenuation process is complex. None of these vaccine projects have yet reached the stage of clinical trials.

2) INACTIVATED SARS-CoV-2 VIRUS VACCINES
Vaccines based on killed microorganisms have been used multiple times in the past for numerous vaccines. While the induced response is generally weaker compared to attenuated viruses, the vaccine is more easily handled, less expensive, and much safer. The SARS-CoV-2 is inactivated by exploiting different chemical techniques.

Seven vaccine candidates based on variously inactivated SARS-CoV-2 virions are in clinical trials, four of which in Phase III trials and already approved for limited use. Most of these are from China apart from our own Bharat Biotech in India, called Covaxin, which is in late-stage Phase III trial.

3) VACCINES BASED ON SARS-CoV-2 PROTEINS
The Spike protein that sticks outside the virus plays an essential role in the docking of the SARS-CoV-2 to human cells. Therefore, the Spike protein or its fragments are targets for these vaccines by using recombinant DNA technology. To activate a robust immune response, often these vaccines exploit adjuvants, either of bacterial or synthetic origin.

At least 16 candidate vaccines are already in human trials and two in Phase II trial: One such vaccine candidate that is carried on nanoparticles is being developed by Novavax, US.

4) DNA-BASED VACCINES
Currently, there are no DNA vaccines registered for human use; however, they are commonly used in veterinary medicine. These vaccines are stable and can easily be produced in large amounts in bacteria. Once injected, DNA plasmids enter human cells, and their ability to enter may be enhanced by a very short local electrical pulse (electroporation). Once entered, plasmid DNA induces the cell to produce temporarily the target protein.

6 DNA vaccines are entering human trials. All code for the Spike protein or its fragments. One such candidate is based on naked DNA plasmids and produced by Zydus Cadila, India and naked DNA plasmids plus electroporation by Inovio, US

5) m-RNA-BASED VACCINES
Messenger RNA (mRNA) has not yet been produced by any registered vaccine so far. Unlike DNA, RNA must be transported in various ways to enter the human cell. Once entered, the mRNA vaccine temporarily induces the cell to produce the antigen protein coded by the mRNA. Also, in the case of anti-SARS-CoV-2 vaccines, the target antigen coded by the mRNA is mostly represented by the Spike protein or its fragments. These vaccines have to be kept at −30 to −80 °C.

There are many vaccine projects based on this technology and two of those have finished Phase III trials- Moderna and Pfizer/BioNTech and are now being widely used in the US.

6) VIRAL VECTOR BASED VACCINES
The DNA coding for the Spike protein can be conveyed into the cells by viral vectors. By inserting the DNA in a harmless virus, it is possible to exploit the virus’s ability to infect and deliver the mRNA into the human cells. Since a preexisting immunity against the virus vector may affect vaccine efficacy, primate viruses (example-chimpanzee) are often exploited as vectors. In other cases, the DNA is inserted into replicating active virus vectors.

4 of these are currently in Phase III trial or approved for use. One such popular one is Chimpanzee adenovirus-based AstraZeneca/Univ. Oxford vaccine. In India, its marketed as Covishield. Recent FDA approved Johnson & Johnson vaccine is human adenovirus-based.

EFFICACY STUDIES

Pfizer/BioNTech vaccine trial involving nearly 44,000 volunteers found vaccination to be 95% effective. Moderna vaccine trial enrolling more than 30,000 volunteers reported an effectiveness of 94%. These are authorized for use in US. AstraZeneca/Oxford vaccine trial reported average effectiveness of 70% with full doses, but even better results (as high as 90%) with a lower dose. This vaccine is authorized for use in Great Britain, India but not in the US yet. Johnson & Johnson trial reported overall effectiveness of 66% (72% in the US) in preventing moderate to severe COVID-19.

All these approved vaccines are effective in decreasing moderate and severe COVID illness and bringing down the need for hospitalization to almost zero. The frequency of side effects is higher than that commonly observed with flu vaccines but most of these are benign. Rarely, a potentially life-threatening reaction called anaphylaxis (trouble breathing, swelling of face and low blood pressure) may occur, most often in people known to have had severe vaccine reactions in the past. About 11 cases per million doses were reported among people receiving the Pfizer/BioNTech vaccine. It usually occurs soon after vaccination, and can be treated with epinephrine (as in an EpiPen). That’s why people are observed for at least 15 minutes after receiving the vaccine with epinephrine ready. A report of 23 deaths among elderly vaccine recipients in Norway raised safety concerns but it’s not clear whether these deaths were related to the vaccines, or represent an expected number of deaths among frail individuals with an already limited life expectancy.

Rare cases of Bell’s (facial muscle weakness) palsy and other neurologic disease have been reported after COVID vaccination. But so far, there is no clear suggestion that the vaccine played any role. Regarding the concerns that the vaccine can cause COVID-19, this can’t happen, because no live SARS-CoV-2 virus is used in currently available vaccines. If a person develops COVID-19 soon after vaccination, it’s not due to the vaccine. It’s either because the vaccine failed (which is rare), or infection developed before the vaccine had a chance to work.

CONCLUSION

Millions of people worldwide have been vaccinated safely till now and it’s our responsibility to take and encourage others to do the same. It is not possible to get a near perfect COVID-19 vaccine that would be effective for all in the world. Each of them would be appropriate in different environmental and human contexts. In the context of polio vaccine, the injectable killed Salk vaccine was effective in industrialized world where polio no longer exists. Whereas the attenuated Sabin vaccine, more effective and easier to be administered orally, is appropriate for the developing world where the wild virus is still circulating. Thus, the evolution of the pandemic could make some vaccines more appropriate in different geographic contexts or for different subsets (e.g., infants, elderly) of the human population.