There are reports of Russia registering world’s first vaccine against novel corona virus while the phase 3 trial of this vaccine is still in progress. Developed jointly by the Gamaleya Research Institute and the Russian Defence Ministry, this vaccine is based on the use of adenovirus vector with embedded genetic material from the coronavirus and introduced into the human body to stimulate an immune response.
There have been reports in the media for some time that vaccines against COVID-19 may be available by the end of 2020.
Has the reported Russian vaccine satisfied all the necessary requirements before being approved for human use? Can we really have a global safe vaccine against COVID-19 before end of this year?
The development of a vaccine in normal course goes through three steps. The first is the discovery research that usually spans 2-5 years followed by pre-clinical development (involving trials on laboratory animals) that takes around 2 years. This is followed by the 3 phases of human clinical trials, the Phase 1 (on healthy volunteers) lasting 1-2 years followed by Phase 2 (localised, on smaller number of patients) that lasts 2-3 years culminating in Phase 3 (multi-centric on large number of patients) that takes 2-4 years. Thus, it takes about ~ 9-10 years to develop a vaccine in normal course. The multi-centric phase 3 of human clinical trial is considered to be an imperative by the regulators because it determines the extent of safety (and efficacy) in a large diverse population spanning across different ethnic groups.
However, in the most extraordinary situations like the current pandemic, the overall timelines can be considerably squeezed in by fast tracking certain steps and processes without compromising the safety (and efficacy if possible) of the vaccine.
So far as the first phase of development of vaccine against COVID-19 is concerned, we have four types based on how viral proteins are expressed in the host to develop an immune response:
- Adenovirus based viral vector vaccine: production of viral proteins inside the host using adenovirus vectors. These viral proteins will act as antigens to elicit an immune response.
- mRNA vaccine: Injecting mRNA directly so that it uses cellular machinery of the host to make viral proteins that will act as antigens thereby triggering an immune response.
- protein-based vaccines: Use of viral expressed proteins outside the host and injecting them as vaccines into human host will trigger immune response by the host.
- Inactivated vaccines: Live vaccines inactivated by heat and/or chemical treatments and injected into the host to develop an immune response.
All the above-mentioned approaches are being tried and tested in parallel.
Given below are few examples of COVID-19 vaccines in development that are either in Phase 2 or Phase 3 human clinical trials.
- ChAdOx1 nCoV-19 vaccine developed along with AstraZeneca has been tested for safety and immunogenicity in a phase 1 / 2 randomised controlled trials. The vaccine showed acceptable safety profile and showed neutralising antibody responses against COVID-19 suggesting that it can be taken further for evaluation in a phase 3 trial.
- mRNA-1273 vaccine, developed by Moderna therapeutics, USA has successfully completed Phase 1 trial of 105 healthy participants followed by a Phase 2 trial of 600 healthy participants evaluating 25 µg, 100 µg, and 250 µg dose levels of the vaccine. mRNA-1273 has now advanced to a Phase 3 trial.
- Covax-19, developed by Vaxine Pty Ltd., has initiated a Phase 1 randomized, placebo-controlled trial of 40 healthy adults aged 18-65 years to assess generation of neutralizing antibodies to the spike proteins of SARS-CoV-2, as well as induction of T-cells against the spike proteins. Phase 2 trials are likely to start by end 2020.
- Covaxin, a COVID-19 vaccine being developed by Bharat Biotech, an Indian biotechnology company, in partnership with the National Institute of Virology is an inactivated vaccine candidate. A Phase 1/2 trial of about 1,100 healthy participants is underway after approval by the Drug Controller General of India.
- Researchers at Sinopharm and the Wuhan Institute of Virology under the Chinese Academy of Sciences are developing an inactivated COVID-19 vaccine candidate that has completed a randomized, double-blind, placebo parallel-controlled Phase 1/2 clinical trial of healthy individuals starting at 6 years old. The vaccine has shown a “strong neutralizing antibody response” in Phase 1/2 trials, and a Phase 3 trial is underway in the United Arab Emirates.
- NVX‑CoV2373, Novavax recombinant protein vaccine has completed Phase 1/2 clinical trial and was generally well-tolerated and elicited robust neutralising antibody responses. The Phase 2 trial to assess immunity, safety, and COVID-19 disease reduction is expected to begin soon.
All the above vaccines have completed pre-clinical and Phase 1 human trials while a few have completed Phase 2 trials as well and Phase 3 is underway.
None of these vaccine candidates have completed phase 3, including the Russian vaccine launched today.
With regard to the vaccine registered by Russia apparently the phase 3 of human clinical trials is in progress. This extraordinary approval without completing the mandatory phase 3 of the trial may be considered unwise because of safety concerns because the non-neutralizing antibodies generated by the vaccine could enhance viral entry into cells and end up worsening infection instead of offering protection, a phenomenon known as antibody dependent enhancement (ADE). Although there is a theoretical possibility of ADE, the degree of ADE vaccine risk for SARS-CoV-2 is unknown.
The urgency of getting the vaccine approved for human use by Russian authorities perhaps takes into account the mental health status of the population due to the pandemic situation and accompanied lockdowns. Assuming that there is possibly only a single strain of virus affecting the Russian population, the adverse effects such as ADE might not be of significance and may not mandatorily require completion of phase 3 clinical trial before vaccine approval. However, a vaccine required for use in the globally diverse population coupled with the existence of multiple variants of the virus, successful completion of multi-centric phase 3 trials becomes mandatory before vaccine approval.
Thus, it seems unlikely to have a vaccine approved for global use by the end of 2020. Even with the fast track level of research and approval, the time line point towards ‘end of 2021’, while factoring in the industrial capacity to produce millions and billions of doses and commercial distribution.