Covid-19 vaccine

                                             Dr. KS Dhillon

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19). It first emerged in December 2019 and the World Health Organization (WHO) declared the outbreak of coronavirus disease 2019 (COVID-19) to be a Public Health Emergency of International Concern on 30 January 2020.  WHO classified it as a pandemic on 11 March 2020. 

As of today, (7/3/21) authorities in 219 countries and territories around the world have reported about 116,822,839 Covid‑19 cases and 2,593,073 deaths [1]. The death rate amounts to 2.17 percent. 

The highest number of cases reported are from the USA where it stands at 27,895,979 cases of Covid-19 with 493,098 deaths. The 2nd highest numbers are from India with 10,963,394 cases and 156,111 deaths. In Malaysia, the figure stands at 274,875 cases with 1,030 deaths [1].

About 80% of COVID-19 patients have mild to moderate symptoms and 20% develop serious manifestations such as severe pneumonia, acute respiratory distress syndrome, sepsis, and even death [2].

The number of COVID-19 cases has increased rapidly around the world.  The causative virus of this ongoing pandemic belongs to the genus Betacoronavirus (β-CoV) of the family Coronaviridae. The other two betacoronavirus are the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle Eastern respiratory syndrome-related coronavirus (MERS-CoV). All these three coronaviruses can produce life-threatening infections. When the SARS and MERS infection appeared there was no such fear and panic that we see today with the Covid-19 pandemic. 

This fear and panic of the Covi-19 pandemic has led to a rush to develop vaccines and not a vaccine to curb the epidemic.

Developing an effective and safe vaccine can take several years. It takes about 10 and 12 years and sometimes longer to develop a safe and effective vaccine. The search for an HIV vaccine has been going since the early 1980s with no success so far. 

There are more than 50 clinical trials worldwide testing potential vaccines, against COVID-19 [3]. To date, 11 vaccines have been approved for use around the world [4].

Usually, vaccines are extensively tested in animals before tests in humans are carried out. 

Due to the urgent need for a vaccine in a surging pandemic, Pfizer and Moderna were given approval to simultaneously test their vaccines on animals while they were conducting Phase 1 trials on humans. The vaccines were tested on mice and macaques.

The Oxford-Astrazeneca(ChAdOX) vaccine protected six monkeys from pneumonia, but the monkeys' noses harbored the same amount of virus as did the noses of unvaccinated monkeys [5]. The developers of the PiCoVacc, a purified inactivated SARS-CoV-2 virus vaccine, from China, reported similar caveats about their vaccine’s early animal tests which they reported in July 2020 [6].

Moderna first published their animal studies in July 2020. They found that viral replication was not detectable in bronchoalveolar-lavage (BAL) fluid by day 2, after challenge in seven of eight monkeys in the vaccinated groups. There was limited inflammation or detectable viral genome or antigen in the lungs of the vaccinated animals. Hence the vaccine did not completely protect the animals against Covid-19 infections [7]. 

There are at least 78 preclinical vaccines that are under active investigation in animals.

Multiple SARS-CoV-2 (Covid-19) vaccines are in development. These include DNA and RNA-based formulations, recombinant subunits which contain viral epitopes, adenovirus-based vectors, and purified inactivated virus [8,9,10]. Traditionally, purified inactivated viruses have been used for vaccine development as was the case with influenza virus and poliovirus. Such vaccines have been found to be safe and effective for the prevention of diseases [11,12]. 

There are three clinical trial phases for efficacy and safety in humans before a vaccine can be approved for use. The most significant difference in the three phases is the scale of testing:

• Phase I, the vaccine is tested on a small group of patients.
• Phase II, the vaccine is tested on larger groups of at least 100 patients and researchers can also test their vaccine in specific subgroups, including people with preexisting conditions, or patients with particular demographic characteristics, such as older age group.
• Phase III, the vaccine is tested on at least 1,000 patients.

There are currently 71 vaccines that are being tested in clinical trials on humans, and 20 of them have reached the final stages of testing. There are 40 vaccines in phase 1 testing, 27 in phase 2, and 20 in phase 3 testing. Six vaccines have been authorized which are in early or limited use. Six have been approved for full use. Four vaccines have been abandoned after initial trials. 

The 6 approved vaccines include Pfizer-BioNTech (mRNA), Moderna (mRNA), Sinovac (inactivated), Cansino (ad5), Sinopharm (inactivated) and J&J (adenovirus) vaccines.

The Pfizer-BioNTech vaccine is Comirnaty (also known as tozinameran or BNT162b2). This vaccine has been approved in several countries. The safety and efficacy study for this vaccine was published in December 2020 [13]. 

In this study a total of 43,548 participants underwent randomization, 43,448 of them received injections: 21,728 with placebo and 21,720 with BNT162b2. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo. This amounted to a 95% efficacy of the vaccine.

There were 10 cases of severe Covid-19 infections with onset after the first dose, 9 of these infections occurred in placebo recipients and 1 in a BNT162b2 recipient.

Four patients among those who received the vaccine had serious adverse events. These included shoulder injury related to vaccine administration, right axillary lymphadenopathy, paroxysmal ventricular arrhythmia, and right leg paresthesia. Two patients in the vaccine group and 4 in the placebo group died. The authors said that the deaths were not related to the vaccine, placebo, or covid-19 infection. The incidence of serious adverse events was similar in the vaccine and placebo groups. It is rather difficult to fathom that a saline injection into the deltoid muscle will produce similar serious adverse events as a vaccine.

In the vaccinated group, 0.036% developed infections and in the placebo group, 0.74% of the patients developed an infection. The number of unvaccinated people developing infections is very small. The number of vaccinated people developing severe infections was 1 and in the unvaccinated group, the number was 9. Vaccination, therefore, does not prevent infections and severe infections but reduces the chances of one developing infection.

All individuals in this study were not followed up with testing for the presence of Covid infection. The individuals were told to report for testing if they developed symptoms of the disease. Many in the vaccinated group may not have reported minor symptoms of the disease thinking that symptoms such as fever, fatigue, and headaches were adverse effects of the vaccine. This could make the final results inaccurate.

The study also did not report the incidence of asymptomatic Covid-19 disease. Hence it is not known if vaccination reduces the incidence of asymptomatic disease which is necessary to prevent the spread of the disease. It is also not known how long the effectiveness lasts. The patients in this study were followed up for 2 months only. It is not known if more vaccinated individuals developed infection after 2 months.

The study was supported by BioNTech and Pfizer and there were some conflicts of interest.

Moderna vaccine trial outcome was published on December 30, 2020 [14]. The trial enrolled 30,420 volunteers in the USA. There were 15,210 participants in the vaccinated group and 15,210 in the placebo group. 

Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group and in 11 participants in the mRNA-1273 group giving an efficacy of the vaccine of 94.1%.

Just as with the Pfizer-BioNTech trial, reactogenicity was more common in vaccine recipients in this trial and that makes it possible that they were less likely to believe that the minor symptoms they had were due to Covid-19 and therefore less likely to refer themselves for testing in the trial. That could have reduced the numbers in the vaccinated group.

Severe Covid-19 infections occurred in 30 individuals, with one fatality and all 30 were in the placebo group. Serious adverse events were rare, and the incidence of adverse events was similar in the two groups. Here again, it is difficult to fathom how a saline injection can produce similar adverse events as a vaccine.

This trial was sponsored and designed by Moderna. The authors had affiliations with Moderna creating conflicts of interest in this publication.

The outcome of the Sinovac vaccine trial was published in November 2020[15]. The primary immunogenic endpoint in this study was seroconversion of neutralizing antibodies to live SARS-CoV-2. The secondary immunogenic endpoints were geometric mean titers of neutralizing antibodies to live SARS-CoV-2, RBD-specific IgG, S-specific IgG, and IgM. 

Seven hundred and thirty-four individuals were eligible for the immunogenic evaluation at the end of 28 days. Seventy-nine percent of the participants seroconverted in the vaccinated group and none in the placebo group. The overall incidence of adverse reactions was 29%. The protective efficacy of Sinovac, however, remains to be determined. 

The outcome of the phase III study for the Sinovac vaccine has not yet been published.

Just as with the Sinovac vaccine, the Johnson and Johnson vaccine was tested for immunogenicity and safety. The study showed that their vaccine Ad26.COV2.S is safe and immunogenic in both younger and older adults. They have not published any phase III outcome study.

The Pfizer-BioNTech and Moderna vaccines were shown to have 94–95% efficacy in preventing symptomatic COVID-19. It does not mean that 95% of people are protected from disease with the vaccine. This is a general misconception of vaccine protection. These efficacy rates are obtained by the following calculations: 100 × (1 minus the attack rate with vaccine divided by the attack rate with placebo) [16].

Simply put, what it means is that in a population such as the one enrolled in the trials, if 1% of unvaccinated individuals developed symptomatic Covid-19 infection, roughly 0.05% of vaccinated individuals will develop symptomatic COVID-19 infection [16].

We are aware that risk reduction was achieved by these vaccines under trial conditions. What we do not know is how it could vary if the vaccines were used for populations with different exposures, transmission levels, and attack rates [16].

The efficacy of these vaccines in preventing severe disease and death is not really known. Protection against severe disease and death is difficult to assess in phase 3 clinical trials because the number of participants are simply too small. To assess efficacy against severe disease and death unfeasibly large numbers of participants are required. Future epidemiological studies may be able to provide such information.

Not all individuals who are exposed to SARS-CoV-2  become infected [17]  and there is heterogeneity in clinical outcomes [18].

The mechanisms, immunological or others, underlying protection or susceptibility to natural infection are not known.

Seroconversion with the presence of antibodies against SARS-CoV-2 is a marker of exposure to Covid-19, but it is not known whether the presence of neutralizing antibodies is sufficient to provide protection against subsequent infection or disease [19]. 

One study showed that a prior history of SARS-CoV-2 infection was associated with an 83% lower risk of reinfection, i.e 17% chance of catching it a second time, with the median protective effect observed five months following primary infection. Sixty-six percent of the 17% who were reinfected were asymptomatic, [20].

In conclusion, vaccination with the Covid-19 vaccine reduces the chance of contracting the disease but it does not prevent a person from contracting the disease. The efficacy of the vaccine in preventing severe disease and death is not known. The incidence of asymptomatic infection after vaccination is also not known. A vaccinated person who contracts the disease can still spread the infection. 

Between 75 and 90% of the population has to be vaccinated to obtain herd immunity. It is unlikely that the vaccines will provide herd immunity in the near future. The need for social distancing rules will continue till the disease disappears with time as did SARS and MERS-CoV. 

Covid-19 vaccines are believed to be generally safe. There have been sporadic reports of death following vaccination but most of the time there is denial that the deaths are due to the vaccine. The latest news report is that

Austria has suspended the AstraZeneca COVID-19 vaccination after the death of one person and illness of another after the shots. The Austrian Federal Office for Safety in Health Care said that currently there is no evidence of a causal relationship between the vaccination and the death and illness [21]. 

References

1. Tracking coronavirus’ global spread, CNN health at https://edition.cnn.com/interactive/2020/health/coronavirus-maps-and-cases/.
2. Z. Wu, J. M. McGoogan, Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72,314 cases from the Chinese Center for Disease Control and Prevention. JAMA 323, 1239–1242 (2020).
3. COVID-19 vaccine development: What's the progress? At https://www.dw.com/en/covid-19-vaccine-development-whats-the-progress/a-55648707.
4. COVID-19 vaccine tracker at https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-vaccine-tracker. 
5. van Doremalen N, Lambe T, Spencer A, Belij-Rammerstorfer S, Purushotham JN, Port JR, Avanzato VA, Bushmaker T, Flaxman A, Ulaszewska M, Feldmann F, Allen ER, Sharpe H, Schulz J, Holbrook M, Okumura A, Meade-White K, Pérez-Pérez L, Edwards NJ, Wright D, Bissett C, Gilbride C, Williamson BN, Rosenke R, Long D, Ishwarbhai A, Kailath R, Rose L, Morris S, Powers C, Lovaglio J, Hanley PW, Scott D, Saturday G, de Wit E, Gilbert SC, Munster VJ. ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques. Nature. 2020 Oct;586(7830):578-582. doi: 10.1038/s41586-020-2608-y. Epub 2020 Jul 30. Erratum in: Nature. 2021 Feb;590(7844):E24. PMID: 32731258. 
6. Gao et al. Development of an inactivated vaccine candidate for SARS-CoV-2 Science 369, 77–81; July 2020.
7. Corbett KS, Flynn B, Foulds KE, et al. Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates. N Engl J Med. 2020;383(16):1544-1555. doi:10.1056/NEJMoa2024671.
8. N. Lurie, M. Saville, R. Hatchett, J. Halton, Developing Covid-19 vaccines at pandemic speed. N. Engl. J. Med. 10.1056/NEJMp2005630 (2020). doi:10.1056/NEJMp2005630pmid:32227757
9. K. Dhama, K. Sharun, R. Tiwari, M. Dadar, Y. S. Malik, K. P. Singh, W. Chaicumpa, COVID-19, an emerging coronavirus infection: Advances and prospects in designing and developing vaccines, immunotherapeutics, and therapeutics. Hum. Vaccin. Immunother. 10.1080/21645515.2020.1735227 (2020). doi:10.1080/21645515.2020.1735227pmid:32186952
10. E. Kim, G. Erdos, S. Huang, T. W. Kenniston, S. C. Balmert, C. D. Carey, V. S. Raj, M. W. Epperly, W. B. Klimstra, B. L. Haagmans, E. Korkmaz, L. D. Falo Jr., A. Gambotto, Microneedle array delivered recombinant coronavirus vaccines: Immunogenicity and rapid translational development. EBioMedicine 102743 (2020). doi:10.1016/j.ebiom.2020.102743pmid:32249203.
11. A. D. Murdin, L. Barreto, S. Plotkin, Inactivated poliovirus vaccine: Past and present experience. Vaccine 14, 735–746 (1996). doi:10.1016/0264-410X(95)00211-Ipmid:8817819
12. C. Vellozzi, D. R. Burwen, A. Dobardzic, R. Ball, K. Walton, P. Haber, Safety of trivalent inactivated influenza vaccines in adults: Background for pandemic influenza vaccine safety monitoring. Vaccine 27, 2114–2120 (2009). doi:10.1016/j.vaccine.2009.01.125pmid:19356614
13. Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, Perez JL, Pérez Marc G, Moreira ED, Zerbini C, Bailey R, Swanson KA, Roychoudhury S, Koury K, Li P, Kalina WV, Cooper D, Frenck RW Jr, Hammitt LL, Türeci Ö, Nell H, Schaefer A, Ünal S, Tresnan DB, Mather S, Dormitzer PR, Şahin U, Jansen KU, Gruber WC; C4591001 Clinical Trial Group. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020 Dec 31;383(27):2603-2615. doi: 10.1056/NEJMoa2034577. Epub 2020 Dec 10. PMID: 33301246; PMCID: PMC7745181.
14. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, Diemert D, Spector SA, Rouphael N, Creech CB, McGettigan J, Khetan S, Segall N, Solis J, Brosz A, Fierro C, Schwartz H, Neuzil K, Corey L, Gilbert P, Janes H, Follmann D, Marovich M, Mascola J, Polakowski L, Ledgerwood J, Graham BS, Bennett H, Pajon R, Knightly C, Leav B, Deng W, Zhou H, Han S, Ivarsson M, Miller J, Zaks T; COVE Study Group. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. 2021 Feb 4;384(5):403-416. doi: 10.1056/NEJMoa2035389. Epub 2020 Dec 30. PMID: 33378609; PMCID: PMC7787219.
15. Zhang Y, Zeng G, Pan H, Li C, Hu Y, Chu K, Han W, Chen Z, Tang R, Yin W, Chen X, Hu Y, Liu X, Jiang C, Li J, Yang M, Song Y, Wang X, Gao Q, Zhu F. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis. 2021 Feb;21(2):181-192.
16. Olliaro P. What does 95% COVID-19 vaccine efficacy really mean? Lancet Infect Dis. 2021 Feb 17:S1473-3099(21)00075-X. doi: 10.1016/S1473-3099(21)00075-X. Epub ahead of print. PMID: 33609458; PMCID: PMC7906690.
17. Bi Q, Wu Y, Mei S. Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study. Lancet Infect Dis. 2020;20:911–919.
18. Docherty AB, Harrison EM, Green CA. Features of 20 133 UK patients in hospital with COVID-19 using the ISARIC WHO clinical characterisation protocol: prospective observational cohort study. BMJ. 2020;369.
19. Long QX, Liu BZ, Deng HJ. Antibody responses to SARS-CoV-2 in patients with COVID-19. Nat Med. 2020;26:845–848.
20. Hall 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 at https://www.medrxiv.org/content/10.1101/2021.01.13.21249642v1.
21. Austria suspends AstraZeneca COVID-19 vaccine batch after death at https://www.thestar.com.my/business/business-news/2021/03/08/austria-suspends-astrazeneca-covid-19-vaccine-batch-after-death.