“Dear World, We have a vaccine. Best news since January 10,” tweeted noted virologist Florian Krammer of the Icahn School of Medicine at Mount Sinai, United States, soon after the two partner companies, Pfizer, U.S., and BioNTech, Germany, announced on November 9 through a press release that the interim results of the phase 3 clinical trials of their novel technology messenger-RNA (mRNA) vaccine against COVID-19 showed an efficacy of over 90 per cent. Some others have called it “a scientific breakthrough”. Vaccine development specialists have termed it extraordinary.
Krammer’s remark was good for a tweet, but in terms of scientific rigour, a press release is not quite the source for detailed information on the trials that epidemiologists and vaccinologists look for. The scientists group involved in the development of the vaccine is yet to post the results on any of the e-print repositories like medRxiv and bioRxiv, let alone publish in a peer-reviewed journal. Considering that the developers had announced the results of phase 1/2 trials of the vaccine candidate BNT-162b1 through medRxiv (“Promising first results” Frontline , August 14), it is surprising that they have not done so for this late-stage trials. Also, the phase 3 trials have, for some unexplained reason, used a variant called BNT-162b2. The project BNT-162 has four variants.
Yet, this would be the first late-stage trial results to come out from among the several vaccine candidates that are undergoing trials the world over, particularly the other promising mRNA vaccine candidate being developed jointly by Moderna Inc. and the National Institute for Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH), U.S. This is quite an achievement in the history of vaccine development, especially against a previously unknown virus. The phase 3 results are out in 10 months as against the normal pace of five-six years. According to media reports, Moderna-NIAID is likely to announce its interim phase 3 results by November end. Also read: BCG as a stop-gap vaccine
The U.S. Food and Drug Administration (FDA) requires a minimum of 50 per cent efficacy in phase 3 trials for a vaccine to be approved for emergency use authorisation (EUA). This is way beyond the lower limit. When the complete phase 3 results are out, while the efficacy figure may go down, it is still likely to be above 50 per cent. If 90-plus per cent efficacy holds well after the completion of trials, it would be on a par with the only known vaccine that has efficacy in this range, the measles vaccine, which is a live attenuated whole virus vaccine. But BNT-162b2 is a new generation vaccine. It is based on the technology of directly delivering the genetic or molecular instructions (the mRNA) for the host system to produce the key antigenic protein of the virus SARS-CoV-2 without itself being infected (Fig. 1). The host immune system recognises this unfamiliar new protein as a foreign body and creates appropriate antibodies. When the real pathogen attacks and presents its antigenic protein in a bid to infect, the immune system can mount an antibody response quickly on the basis of its memory trained through vaccination. It should be noted that no mRNA vaccine has been approved for public use.
Russia’s claim
But in this global scientific and commercial race for the first shot of the COVID-19 vaccine, play of geopolitics is very much in evidence. Not to be outdone by the West, the Gamaleya Research Institute for Epidemiology and Microbiology of the Russian health ministry issued a press release on November 11 on the interim results of phase 3 trials of its vaccine Gam -COVID-Vac (Sputnik-V). It has claimed 92 per cent efficacy.
Gamaleya’s announcement of its candidate vaccine and its phase 1/2 results came as a reactive response. As soon as the other vaccine frontrunners, such as Oxford-AstraZeneca, Moderna-NIAID and Pfizer-BioNTech, came out with their phase 1/2 results in July, Russian President Vladimir Putin made a public announcement, on August 11, of Sputnik-V. Gamaleya announced its phase 1/2 results thereafter, and this was followed up by a publication in the journal The Lancet on September 4. Gamaleya clearly had complete data from the phase 1/2 trials for it to be published quickly. Also read: Quest for a Covid vaccine
But, given the responses of the stock market of the West to such premature announcements through press releases, it would seem that this game of one-upmanship is driven by commercial interests rather than science and a sincere effort at finding a rigorously evaluated effective vaccine to end the pandemic.
The Sputnik vaccine
Although the Russian vaccine was briefly mentioned in an earlier article in Frontline (“Race for immunity”; October 23), it had not been adequately described, which we do here for completeness.
Sputnik-V is a two-component (or heterologous) recombinant viral-vector vaccine with two different human adenoviral vectors, both carrying the gene for SARS-CoV-2’s antigenic spike protein. The vaccine uses a prime-boost regimen with the recombinant-adenovirus Ad26 (rAd26) component priming the immune response followed by the recombinant Ad5 (rAd5) component given after a three-week period boosting the response (Fig. 2).
The CanSino vaccine (CanSino Biologicals, China), too, is a recombinant viral-vector vaccine but it uses human Ad5 as the vector ( Frontline ; “Promising first results”; August 14) and the regimen involves two doses of the same. Similarly, the recombinant vaccine of Johnson & Johnson, U.S., uses Ad26 as the vector. The Oxford-AstraZeneca vaccine ChAdOx1, on the other hand, uses a chimp adenovirus vector in a two-dose regimen. Unlike the vaccine of Pfizer-BioNTech or Moderna-NIAID, which injects the genetic instructions for the host to make the antigenic protein, the viral-vector vaccines inject the antigenic protein or parts of it directly through a genetically engineered viral-vector as the carrier.
The uniqueness of the Russian vaccine lies in its use of two different human adenovirus vectors. This, according to Gamaleya, helps provide strong and long-term immune response after the second injection. The other important feature of the vaccine is its freeze-dried or lyophilised formulation, which enables easy delivery across regions and countries. The development of the vaccine is supported by the Russian Direct Investment Fund (RDIF), the country’s sovereign wealth fund.
Gamaleya conducted two open, phase 1/2 non-randomised trials of two formulations of the vaccine (frozen and freeze-dried) in 76 healthy adult volunteers (38 each for the two studies using the two formulations) between June 18 and August 3. According to The Lancet paper, the study included both civilian and military volunteers. The military personnel, it clarified, were contract employees and not individuals conscripted for compulsory military service. While the study of frozen formulation was done at a branch of Burdenko Hospital, an agency of the Ministry of Defence, that with the freeze-dried formulation took place at Sechenov University, and all volunteers in that study were civilians.
The safety of the two individual vaccine components (rAd26 and rAd5) was confirmed in phase 1. Both components were then administered as a prime-boost vaccination in phase 2, which included testing for safety and immunogenicity. The vaccine, according to The Lancet paper, was well tolerated and produced humoral and cellular immune responses in all the recipients. IgG responses were elicited in all participants, with geometric mean titres significantly higher than those reported in the convalescent blood plasma of people who had recovered from COVID-19. All reported adverse events during the trials were mostly mild and the adverse event profile did not differ from those reported for other viral-vector-based vaccines. Also read: The vaccine race
The paper had also stated that approval for its phase 3 trials in over 40,000 individuals was granted on August 26. However, Putin went one step further by playing the West’s own game by authorising on August 11 conditional public use of this vaccine under the EUA mechanism solely based on its phase1/2 results even before phase 3 trials had been authorised. It became the first COVID-19 vaccine in the world to be registered for civil use. This drew widespread criticism from the world scientific community, including the Moscow-based Doctors’ Alliance.
The Russian government responded aggressively to such criticisms. An official website www.sputnikvaccine.com was established with the aim, as it states, “to provide accurate and up-to-date information about the vaccine and to combat the misinformation campaign launched against it in the international media”. In an op-ed, available for any outlet to use, the website says “Instead of looking into the science behind the proven adenoviral vector-based vaccine platform [that] Russia has developed, some international politicians and media chose to focus on politics and…undermine the credibility of the Russian vaccine. We believe that such an approach is counter-productive and call for a political “ceasefire” on vaccines in the face of COVID-19 pandemic.”
According to the Gamaleya press release, in September this vaccine was first given to a cohort group of volunteers from the “red zones” of Russian hospitals distinct from the phase 3 trial recruits. The observation of additional 10,000 volunteers representing medics and other high-risk groups, who were vaccinated under the authorised civil use programme, had also indicated an efficacy of over 90 per cent. Following this, the RDIF CEO, Kirill Dmitriev, stated through a September press release that preliminary results of Sputnik-V’s efficacy (phase 3) trials would be available by October-November.
Pfizer-BioNTech trials
In their joint press release, Pfizer and BioNTech claimed that, on the basis of the first interim efficacy analysis of the phase 3 trial results conducted on November 8 by an external independent data monitoring committee (DMC), their vaccine candidate BNT-162b2 had shown an efficacy rate of above 90 per cent in participants with no evidence of SARS-CoV-2 infection. As the online publication STATNews observed, this strategic move on the part of the developers to allow an external monitoring committee to have an early look at the findings was a well planned one to ensure that theirs would be the first to bring the late-stage trial data to the public.
The trial, which began on July 27, was a double-blind randomised one that included 43,538 volunteers (of ages above 16 with 40 per cent being 55 or older). About half of them were to get the vaccine (administered intramuscularly) and the rest a placebo. As of November 8, of the total, 38,955 had received the second dose as well. According to the release, about 42 per cent of global participants and 30 per cent of U.S. participants had racially and ethnically diverse backgrounds. The companies also stated that no serious safety concerns had emerged so far.
The efficacy claim is based on an analysis of 94 people who contracted the infection after being administered either the vaccine or the placebo. According to the release, the interim analysis was initially intended to be done when the number of symptomatic cases touched 32. According to STATNews , the companies had originally proposed to announce that the vaccine was effective if fewer than six vaccinated volunteers had caught the infection and became symptomatic (80-85 per cent efficacy). But this seems to have been rejected by the FDA and it was then decided in late October that the announcement would be made at a minimum of 62 symptomatic cases. But by the time the discussions with the FDA were concluded, the evaluable number of COVID cases apparently had already touched 94, and the DMC was called upon to analyse the data. This implies that the efficacy data (with 94 cases) are statistically stronger than what the developers had expected.
The data showed that, with the case split between the vaccinated group and the placebo group, the efficacy of the vaccine was above 90 per cent at seven days after the second dose, which was 21 days after the first in the two-dose vaccination schedule. But what the announcement did not state is how many of the infected were in the vaccinated group and how many in the placebo group. But given the stated efficacy of over 90 per cent, the split ratio would be roughly 8(or 9):86(or 85).
The study, according to the trial design, would be concluded once the infected number hits 164. Clearly, the final efficacy would change. But scientists expect it to remain in that range at the end. “I’ve been in vaccine development for 35 years,” William Gruber, Pfizer’s senior vice president, told STAT. “I’ve seen some really good things. This is extraordinary…This really bodes well for us being able to get a handle on the epidemic and get us out of this situation.”
For the final analysis, the release says, in addition to primary endpoint of vaccine efficacy at the end of seven days of the second dose, it will also determine, with the permission of the FDA, the efficacy from the cases accruing 14 days after the second dose. The companies believe that this secondary endpoint will help align its data with all COVID-19 vaccine studies and allow for cross-trial learning and comparison of performance between novel technology vaccine platforms. Also read: Race for immunity
According to the FDA guidelines, for a vaccine to be authorised for EUA, half the participants in the study have to be monitored for at least two months after the second dose. The companies, according to the release, expect to reach that milestone by November end. On the basis of their current projections, the companies hope to be able to produce up to 50 million doses in 2020 and up to 1.3 billion doses in 2021. The results of the complete phase 3 trial will be submitted for peer review and publication, the release said. In any case, it should be clear that the vaccine, if found to be safe and efficacious, will be available only by mid-2021.
But the released data about the Pfizer-BioNTech vaccine’s performance in the trials are sparse. Key information that has not been revealed is whether the vaccine prevented vaccinated people from developing symptoms or whether it prevented the infection itself. In particular, we do not know if the vaccine is capable of preventing asymptomatic infection and transmission of the virus by them. Also, though the participants included the elderly (above 65) as well, the released information does not tell us the age stratified data of the 94 symptomatic cases seen; does it significantly reduce the disease among the aged and people with co-morbidities? What was the spectrum of the disease or the extent of illness seen in the 94 cases? By how much does it reduce severe disease, subsequent hospitalisation and death? Also, one does not know how long the protection conferred by the vaccine will last.
One of the huge challenges lies in delivering the vaccine to millions of people. Unlike the Gamaleya vaccine, it is not a freeze-dried vaccine. In its frozen form, it needs to be kept at the ultra-low temperature range of −70-80° Celsius. The cold chain for most vaccines in use requires temperatures of about −15°C. A handful of vaccines require about −50° C. But this mRNA vaccine would need temperatures significantly lower, which would pose a major challenge to available infrastructure even at medical centres in advanced countries. Also read: The Rotavirus vaccine
Landmark success
Nevertheless, this landmark success for a new technology vaccine would boost the confidence of other advanced technology vaccine developers. In India, two mRNA vaccine trials have been approved for trials, one by the Christian Medical College, Vellore, and the other called HGCO19 by a Pune-based drug company Gennova Biopharmaceuticals, which has collaborated with a Washington-based company, HDT Biotech Corporation. Both have been funded by the Biotechnology Industry Research Assistance Council (BIRAC) of the Department of Biotechnology (DBT). These vaccines use lipid encapsulated formulations as the vehicle to inject the mRNA vaccine. Gennova-HDT’s mRNA vaccine uses inorganic lipid nanoparticle encapsulation which, reportedly, does not require ultra-low temperatures for stability— apparently storing it in the 2-8° C temperature range would suffice, thus obviating serious transportation and delivery issues.
Sputnik-V’s phase 3 results are based on the first interim data of a large double-blind, randomised placebo-controlled trial involving 40,000 volunteers spread over Russia’s 29 medical centres. As of November 11, over 20,000 volunteers had received the priming dose and over 16,000 had received both the prime and boost doses. According to the Gamaleya press release, the trials evaluated efficacy among the16,000-plus participants who received the vaccine or placebo 21 days after the first injection.
Analysis of the 20 confirmed cases of COVID-19 split between the vaccinated and placebo groups indicated that the vaccine had an efficacy of 92 per cent, the release stated. It said no adverse events were seen except for mild short-term side-effects. An independent committee is monitoring the safety of the vaccine. The study is expected to continue for six months. A separate study of the vaccine’s safety and immunogenicity in the elderly is on. Like in the case of the Pfiszer-BioNTech vaccine, trial data are sparse in Sputnik-V, too, but the release says that the complete trial report will be made public after the completion of phase 3 trials. Also read: Lessons from a vaccine
Currently, phase 3 trials are stated to be on in Belarus, the UAE and Venezuela, and phase 2/3 trials in India (by Dr. Reddy’s Labs) have been approved. The vaccine has been received here, and trials, to be supported by BIRAC, are expected to begin shortly. According to Dmitriev, requests for more than 1.2 billion doses of Sputnik-V have been received from over 50 countries. The vaccine supplies for the global market, he said, would be produced by RDIF’s international partners.
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