COVID-19 Vaccines – Comprehensive Review

Dr Swapnil Pawar February 28, 2021 688 1

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    COVID-19 Vaccines – Comprehensive Review
    Dr Swapnil Pawar

COVID-19 vaccines: Comprehensive Review

Written by – Dr Jose Chacko

Several vaccines are being employed against COVID-19 following expedited evaluation and manufacturing processes. Currently, more than 50 potential vaccines are undergoing clinical trials in various phases.1 Effective immunization is considered to be an important strategy in the control of the COVID-19 pandemic.

Phases of vaccine development

The conventional methodology of vaccine development involves several phases. The first step in the process involves preclinical evaluation. During this phase, the vaccine is administered to experimental animals to evaluate immunogenicity and toxicity. Clinical trials follow in three phases if an immune response is obtained in the preclinical stage. Phase I primarily involves assessment of safety, besides evaluation of the immune response. Phase I trials comprise sample sizes of up to 100 subjects, usually in the adult age group. During this phase, the appropriate dose of the vaccine may also be evaluated. Seamless progression to phase II usually follows, with continued assessment of safety and immune response, in a much larger number of individuals, usually several hundreds.

Phase III trials are crucial and examine the capability of the vaccine candidate to prevent laboratory-confirmed disease in a randomized, placebo-controlled design of adequate sample size. Vaccine efficacy is calculated as the incidence of the disease in the control group – incidence of the disease in the vaccine group/incidence of the disease in the control group (expressed as a percentage).

Types of vaccines – the “whole microbe” approach

The “whole microbe” approach involves using the whole SARS-COV-2 virus or a vector to stimulate an immune response. This may be of three types:

Inactivated virus

The SARS-CoV-2 virus is grown in cell culture followed by chemical inactivation. An adjuvant such as alum is combined with the inactivated virus to evoke an immune response. The immune response generated targets several viral components, including the spike protein. Covaxin, produced by Bharath Biotech in India, is an inactivated vaccine and is being used in several states in India. This vaccine is currently being evaluated in a phase III clinical trial.

Live attenuated vaccine

The virus is genetically modified or grown in adverse conditions that abolishes virulence, but maintains immunogenicity when administered as a vaccine. A live attenuated vaccine triggers humoral and cellular immunity to several components of the virus. Besides, live attenuated vaccines may be administered intranasally. Intranasal administration has the added advantage of evoking a local immune response in the respiratory tract mucosa. Mucosal vaccines generate IgA antibodies in the respiratory mucosa and may prevent colonization and infection, unlike systemically administered vaccines, which primarily reduce the severity of infection. Intranasal administration of live attenuated vaccines may thereby reduce transmission of the disease in the community. Nasal vaccines are currently undergoing preclinical and phase I studies. Covi-Vac is live attenuated nasal vaccine being studied, jointly by Codagenix in the US and the Serum Institute of India

Viral vector vaccines

Vector vaccines use a different, safe virus that delivers genetic material of the pathogenic virus. The host cells make use of the genetic material to create specific protein components of the pathogenic virus. With SARS-CoV-2 vaccines, the spike protein is produced by the host cells using genetic material delivered by the vector virus. The immune system generates antibodies against the spike protein, thus stimulating the immune cells to defend against SARS-CoV-2 infection. The vector viruses are harmless and do not usually cause disease in humans. The Oxford-AstraZeneca vaccine uses a chimpanzee adenovirus as the vector that expresses the SARS-CoV-2 spike protein. Another vector vaccine is the Russian Sputnik V vaccine.

Nucleic acid vaccines

Nucleic acid vaccines employ a novel approach; they do not use whole or part of the viral pathogen. Instead, the genetic material of the virus is administered. This genetic material is coded to produce the SARS-CoV-2 spike protein by the host cells. This leads to the triggering of an immune response. The nucleic acid platform is used in the Pfizer and Moderna vaccines. Both these vaccines use mRNA as the genetic material. The mRNA remains confined to the cytoplasm without entering the nucleus of the cell. Besides, the mRNA does not integrate into the host DNA. mRNA vaccines are manufactured in vitro, enabling rapid production; however, they require storage at very low temperatures leading to logistic problems in many parts of the world.

Recombinant protein vaccines

Protein-based vaccines use the recombinant spike protein of the SARS-CoV-2 virus that generates an immune response.  The Novavax vaccine uses recombinant protein technology and has undergone phase III clinical trials at the time of writing.

Clinical studies of COVID-19 vaccines

The quest for an effective vaccine against COVID-19 began with the first clinical trials in March 2020. Several vaccines have completed late phase clinical trials and are being extensively used across the globe.

BNT162b2 (Pfizer)

This is an mRNA vaccine delivered through a lipid nanoparticle and expresses the SARS-CoV-2 spike protein. The Pfizer vaccine was studied in a large, placebo-controlled randomized controlled trial of 36,000 subjects. Two doses were administered 21 days apart. The vaccine was effective in preventing symptomatic infection with 95% efficacy starting 7 days after the second dose. Symptomatic COVID-19 infection occurred in 162/21,728  (0.74%) subjects in the placebo group compared to 8/21,720 (0.03%) who received the vaccine. Vaccine efficacy at preventing symptomatic infection was noted from 2 weeks after the first dose.2

Mild adverse effects were common, especially after the second dose, and occurred more often in younger subjects. Anaphylactic reaction to the vaccine has been estimated to be approximately 11 per one million doses.

mRNA 1273 (Moderna)

The Moderna mRNA vaccine was evaluated in a phase III randomized controlled trial using two doses, administered 28 days apart. In this study of 30,420 subjects, symptomatic Covid-19 infection occurred in 185/15,210  participants in the control group compared to11/15,210 participants in the vaccine group with an overall efficacy of 94.1%. Thirty individuals developed severe illness, all in the control group. Vaccine efficacy was 80.2% among 2000 subjects who received a single dose of vaccine.

Local and systemic adverse effects were common after the second dose; most were mild or moderately severe in nature. Adverse effects were less frequent among older individuals. Anaphylactic reaction to the vaccine is estimated to be 2.5 events per million doses.3

ChAdOx1 nCoV-19/AZD1222 (Oxford-AstraZeneca)

The Oxford-AstraZeneca vaccine uses a chimpanzee adenovirus as the vector; the vector virus expresses the SARS-CoV-2 spike protein, which evokes the immune response. This vaccine is being extensively administered in India, and has been approved for use in several countries, including the United Kingdom, Brazil, and the European Union.

The Oxford-AstraZeneca vaccine was evaluated in a multinational phase III randomized controlled trial conducted in the UK, Brazil, and South Africa and the preliminary results have been published.4 Two doses of the vaccine were administered 28 days apart. The primary efficacy analysis was the development of symptomatic COVID-19 in seronegative participants starting from 2 weeks after the second dose of the vaccine. The vaccine revealed an efficacy of 62·1% in patients who were administered two standard doses of the vaccine. A subgroup of patients in the UK inadvertently received a low dose as the first dose, followed by a standard dose. The low dose–standard dose regime seemed to bestow a higher level of protection (90·0%), although the difference was not statistically significant compared to the two standard doses regime. The overall efficacy of both groups combined was 70.4%. Beginning 21 days following the first dose, ten patients required hospitalization due to COVID-19, all in the control arm. The incidence of severe adverse events was not different between the vaccine and the control groups.

BBV152 (Covaxin)

BBV152 is an inactivated virus-based SARS-CoV-2 vaccine developed by Bharath Biotech in collaboration with the Indian Council of Medical Research. This vaccine has undergone phase I and II trials and is currently being evaluated in a phase III trial.

In a phase II trial, the immunogenicity and safety of Covaxin were evaluated.5 Three hundred and eighty subjects, including adults and children, received one of two formulations: 3 or 6 μg preparations adsorbed to alum (Algel-IMDG). Two doses were administered at a 4-week interval. Among 380 participants randomized, seroconversion with neutralizing antibodies on day 56 was 92·9% and 98·3% with the 3 μg and 6 μg formulations. Both doses resulted in a higher Th1 (proinflammatory) compared to Th2 (anti-inflammatory) cytokine response. Serious adverse effects were not observed in this study. Follow up analysis on day104 revealed seroconversion in 73·5% subjects in the 3 μg and 73·1% of subjects in the 6 μg group.

Gam-COVID-Vac (Sputnik V)

Gam-COVID-Vac is a viral two-vector vaccine based on two human adenoviruses – a common cold virus – containing the gene that encodes the full-length spike protein (S) of SARS-CoV-2 to stimulate an immune response. The Gam-COVID-Vac vaccine was developed by a cellular microbiologists team of the government-backed Gamaleya Research Institute of Epidemiology and Microbiology. The recombinant adenovirus types 26 and 5 are both used as vectors in the vaccine. They were biotechnology-derived and contain the SARS-CoV-2 S protein cDNA.

Gam-COVID-Vac is a combined vector vaccine, based on rAd (recombinant adenovirus) type 26 (rAd26) and rAd type 5 (rAd5)— both of which carry the gene for SARS-CoV-2 full-length glycoprotein S (rAd26-S and rAd5-S). rAd26-S and rAd5-S are administered intramuscularly separately with a 21-day interval.

When using vector-based vaccines, immune responses are formed not only to the target antigen but also to the vector component. As a result, the best vaccination scheme is heterologous vaccination, when different viral vectors are used to overcome any negative effects of immune response to vector components.

This vaccine was studied in a placebo-controlled, phase 3 trial at 25 centers in Moscow. Adult patients 18 years older, who tested negative for SARS-CoV-2 PCR and IgG and IgM were the subjects of this study. Study subjects were randomly in a 3:1 ratio to receive vaccine or placebo. Two doses of the vaccine were administered intramuscularly at 21 days apart.

The primary outcome was the number of subjects with COVID-19 confirmed by RT-PCR from 21 days after the first dose. Overall, 19 866 participants received two doses of the vaccine or placebo. Beginning 21 days after the first dose, 16/14 964 (0·1%) participants in the vaccine group and 62/4902 (1·3%) in the placebo had confirmed COVID-19 infection. The vaccine efficacy was 91·6% (95% CI 85·6–95·2). Most reported adverse events were grade 1 (7485 [94·0%] of 7966 total events). 45 (0·3%) of 16 427 participants in the vaccine group and 23 (0·4%) of 5435 participants in the placebo group had serious adverse events; none were considered associated with vaccination, with confirmation from the independent data monitoring committee. There were 4 deaths, 3 in the vaccine group, considered unrelated to the vaccine and 1 death in the placebo group. Serious adverse events occurred in 0.3% and 0.4% of subjects in vaccine and placebo groups respectively; none were considered vaccine-related, as confirmed by an independent data monitoring committee.

Recent phase 3 trials

NVX-CoV2373 (Novavax) is a recombinant full-length spike protein vaccine. According to a press release by the company6, the UK segment of the phase 3 trial involved 15,000 subjects. Fifty-six cases of COVID-19 were identified in the placebo group compared to six cases in the vaccine group, with an overall 89.3% efficacy. The efficacy against the original SARS-CoV-2 strain was 95% compared to 85% against the B117 UK variant. The South African phase IIb trial enrolled over 4,400 patients. The efficacy was down to 60% against the South African B1351 variant strain, suggesting that COVID-19 vaccines may struggle to protect against this strain. This is the first efficacy study of a protein-based vaccine.

The Janssen vaccine (Ad.26.COV2.S or JNJ-78436725) uses the human adenovirus as a vector for the expression of the SARS-CoV-2 spike protein. This vaccine requires only a single intramuscular dose and can be stored in a refrigerator for several months. According to the press release by the company, the interim analysis included 468 cases of symptomatic COVID-19 among 44,325 subjects enrolled in South America, the United States, and South Africa. Argentina. The vaccine was reported to be 66% effective at achieving the endpoint of preventing moderate and severe COVID-19 at 28 days post-vaccination.7

Other vaccines

The Russian vaccine, Sputnik V, is an adenovirus vector vaccine. An efficacy of 91.4% has been reported on an interim analysis of a small sample in a phase III trial. Sinopharm and Sinovac are inactivated virus-based vaccines from China; both are administered as two doses, 28 days apart. Sinopharm has been approved for use in the United Arab Emirates based on a phase III efficacy data from that country.

Unanswered questions and future targets

Vaccination triggers two types of immune response. Most current vaccine research against SARS-CoV-2 aims to generate neutralizing antibodies. However, a robust neutralizing antibody response alone may be insufficient to prevent severe disease. Besides, antibodies may worsen pathology instead of being protective, as evident from studies in patients with the Middle East Respiratory Syndrome (MERS).8 The presence of antibodies may also lead to more severe disease by the phenomenon of antibody-dependent disease enhancement as seen with coronavirus infections in animals.9 A robust T cell response may be crucial in the development of protective immunity.10 Besides a strong neutralizing antibody response, an appropriate level of memory CD8 T cell response with the generation of Th1 cytokines needs to be evaluated with future vaccines.


  • Vaccination is an important cog in the wheel in a multifaceted approach to bring the COVID-19 pandemic to an end
  • Vaccines that are currently approved for clinical use offer a high level of protection against severe COVID-19 infection
  • Vaccines approved for clinical use undergo preclinical, followed by three phases of clinical trials
  • Commonly employed vaccine platforms include inactivated whole virus, vector viruses, recombinant spike protein, and nucleic acid vaccines
  • Several vaccines, including Pfizer, Moderna, Oxford-AstraZeneca, Novavax, and Janssen have undergone phase III trials. The Oxford-AstraZeneca and Covaxin are authorized for clinical use in India
  • An effective COVID-19 vaccine should elicit a robust T cell response in addition to the generation of neutralizing antibodies


1. COVID-19 vaccines. Accessed January 27, 2021.

2. Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020;383(27):2603-2615. doi:10.1056/NEJMoa2034577

3. Baden LR, El Sahly HM, Essink B, et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. 2020;0(0):null. doi:10.1056/NEJMoa2035389

4. Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. The Lancet. 2021;397(10269):99-111. doi:10.1016/S0140-6736(20)32661-1

5. Ella R, Reddy S, Jogdand H, et al. Safety and Immunogenicity Clinical Trial of an Inactivated SARS-CoV-2 Vaccine, BBV152 (a Phase 2, Double-Blind, Randomised Controlled Trial) and the Persistence of Immune Responses from a Phase 1 Follow-up Report. Infectious Diseases (except HIV/AIDS); 2020. doi:10.1101/2020.12.21.20248643

6. Novavax COVID-19 Vaccine Demonstrates 89.3% Efficacy in UK Phase 3 Trial | Novavax Inc. – IR Site. Accessed January 30, 2021.

7. Johnson & Johnson Announces Single-Shot Janssen COVID-19 Vaccine Candidate Met Primary Endpoints in Interim Analysis of its Phase 3 ENSEMBLE Trial | Johnson & Johnson. Content Lab U.S. Accessed January 30, 2021.

8. Zhao J, Alshukairi AN, Baharoon SA, et al. Recovery from the Middle East respiratory syndrome is associated with antibody and T-cell responses. Sci Immunol. 2017;2(14). doi:10.1126/sciimmunol.aan5393

9. Vennema H, de Groot RJ, Harbour DA, et al. Early death after feline infectious peritonitis virus challenge due to recombinant vaccinia virus immunization. J Virol. 1990;64(3):1407-1409. doi:10.1128/JVI.64.3.1407-1409.1990

10. Ahmed R, Akondy RS. Insights into human CD8+ T-cell memory using the yellow fever and smallpox vaccines. Immunol Cell Biol. 2011;89(3):340-345. doi:

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