I n the issue of Frontline dated December 4, we reported the highly promising interim results of Phase-3, or late-stage, trials of Pfizer-BioNTech’s new technology mRNA vaccine (named BNT-162b2), which, the collaborating companies claimed on November 9 in a press release, had shown over 90 per cent efficacy.
This announcement was immediately followed by an announcement on November 11 by Russia’s state-sponsored vaccine developer Gamaleya Research Institute that the interim Phase-3 results of its vectored-vaccine (Gam-COVID-Vac or Sputnik V) had shown 92 per cent efficacy.
A week after Pfizer-BioNTech announced its results, Moderna, a new United States drug company which is pioneering the same technology as the former two, in collaboration with the U.S. National Institute of Allergy and Infectious Diseases (NIAID), issued a press release in which it claimed that the interim results of the Phase-3 trials of its vaccine (mRNA-1273) had shown 94.5 per cent efficacy. Two days later, on November 18, Pfizer-BioNTech announced that in the final results of the concluded Phase-3 trials, the vaccine efficacy was found to be 95 per cent, markedly higher than the 90+ per cent claimed after the interim analysis.
And the latest among the frontrunners to announce its results is the Oxford University Vaccine Group (OVG), which is partnering with the British-Swedish drug company AstraZeneca to develop, like Gamaleya of Russia, a vectored-vaccine (ChAdOx1-nCOV; also called AZD1222). The vaccine uses a recombinant simian adenovirus as the vehicle to deliver SARS-CoV-2’s antigenic S-protein. A vaccine based on this technology has never won approval for public use. But the approach has been studied before, notably in a small 2018 study of an experimental vaccine against Middle East Respiratory Syndrome (MERS). The MERS virus is related to SARS-CoV-2 which causes COVID-19.
Oxford University stated on November 23 that the interim results of its Phase-3 trials showed that the vaccine was 90 per cent efficacious with one particular vaccine dose regimen and only 62 per cent with another dose regimen, giving a weighted average efficacy of 70.4 per cent. This means that the Oxford-AstraZeneca’s AZD1222 is potentially 90 per cent efficacious.
Efficacy and effectiveness
Clearly a race to the finishing line, with all eyes on the market, is on. To begin with, all the three developers—Pfizer-BioNTech, Moderna-NIAID and Oxford-AstraZeneca—have stated that they would be seeking Emergency Use Authorisation (EUA) approval for their vaccines wherever they plan to deliver or deploy immediately for use among select cohort groups, like health-care workers and other susceptible populations.
Before we discuss the details of the latest announcements by the three frontrunners, a couple of clarifications are in order.
As vaccinologist Florian Krammer of the Icahn School of Medicine at Mount Sinai in the U.S. has emphasised, although efficacy and effectiveness are often used interchangeably in popular discourse about vaccines, the two are different. Efficacy refers to vaccine performance observed in idealised laboratory conditions in a limited number of healthy individuals (including Phase-3 that involves tens of thousands of people), conditions that are not obtained during deployment as a public health measure.
Vaccine deployment in the real world involves large community populations across nations with enormous racial and ethnic diversity and with widely varying health and innate immunity status. Besides, issues arising during industrial-scale bulk manufacture of millions of doses and meeting the specified storage and delivery standards, particularly cold-chain requirements, would also have an impact.
Vaccine performance in the real-world scenario is termed as effectiveness, which is bound to be significantly lower than what is observed in trials. As data continue to be gathered after the vaccines are rolled out (Phase-4), the efficacies could drop by 10-20 percentage points. From the perspective of the currently raging pandemic, efficacy in the 90s percentage range was beyond the expectations of most vaccinologists. They would consider even 70 per cent effectiveness as very good. The influenza vaccine in public use, for example, averages an effectiveness of about 45 per cent only.
In the earlier article, it was noted that the variant of the mRNA vaccine construct that Pfizer-BioNTech used in Phase-3 was different from the one used in Phase-1/2 trials, the basis of which was not clear at the time of writing the article. With subsequent literature search, it has become clear that the difference between the two is crucial and the choice was made following a comparative study between the two.
In the vaccine variant BNT-162b1, which was used in Phase-1/2, the injected (lipid encapsulated) mRNA encoded genetic instructions for the host to produce only a part of the spike protein called the receptor binding domain (RBD). The b2 variant, on the other hand, carries the code for the full-length S-protein. In a separate randomised clinical trial involving 195 participants, Pfizer-BioNTech compared the two variants and found that the incidence and severity of side effects were lower in those vaccinated with the variant BNT-162b2, particularly in the elderly (aged 65-85), than in those vaccinated with BNT-162b1.
These findings were published on October 14 in the New England Journal of Medicine (NEJM). Following this study, the b2 variant was chosen for the Phase-3 trials. This makes the Pfizer-BioNTech vaccine much more similar to the mRNA vaccine of Moderna-NIAID, whose construct also encodes for the entire S-protein.
The Pfizer-BioNtech vaccine
Pfizer-BioNTech’s interim result of over 90 per cent efficacy was based on an analysis of 94 COVID-19 patients (from both vaccinated and placebo groups)—status measured in each case 28 days after the first dose (equivalently, seven days after the second dose)—from a total of 43,661 volunteers who were divided equally into the two groups. The participants were aged above 16 with 40 per cent being 55 or more. Of these, 41,135 had completed their two doses of the prime-boost regimen of the vaccine as of November 13, as against 38,955 on November 9.
(It may be noted that in the press release giving the interim results of Phase-3 trials on November 9, the total number of participants had been stated as 43,538. The reason for this increased number has not been stated.)
The trial was scheduled to be concluded when the COVID-positive number would touch 164. The concluding results announced on November 18 are based on the analysis of 170 COVID-19 cases, six more than the targeted number. It is interesting to note that the number was reached within 10 days of interim results, an indication of how the infections worldwide continue to rise at a rapid rate. Of the 170, 162 were from the placebo group and eight from the vaccinated group, implying an efficacy of over 95 per cent.
The press release also stated the “efficacy was consistent across age, gender, race and ethnicity demographics”. In all, there were about 150 trial sites across the U.S., Germany, Turkey, South Africa, Brazil and Argentina, with 39 from the U.S. alone. About 42 per cent of global and 30 per cent of U. S. volunteers were from diverse ethnicities and 41 per cent of global and 45 per cent of U.S. participants were 56-85 years of age.
The vaccine was found to be tolerated across all populations and the only “Grade 3” or severe adverse event—which interferes with one’s ability to do day-to-day work—greater than 2 per cent in frequency was fatigue at 3.8 per cent and headache at 2 per cent, according to the release. There was no serious safety concern either. To assess this, a separate unblinded study was done in a randomised subset of 8,000 volunteers (aged above 18), which found that most of the adverse events seen were mild and they were resolved shortly after vaccination.
Significant efficacy among elderly
A significant claimed result is that the vaccine was found to be over 94 per cent efficacious in adults over 65 years of age. The other equally significant result is that out of the 10 severe cases of COVID that were seen, nine were in the placebo group and one in the vaccinated group. So, the vaccine is highly efficacious among the elderly, a feature not usually seen in conventional vaccines as, with age, immune responses gradually decline, due to what is known as immuosenescence.
Secondly, it seems to prevent the disease becoming severe. The companies have also said that the trial would continue to collect efficacy and safety data for an additional two years.
Following the success of the Pfizer-BioNTech vaccine as the first global trial to reach the final efficacy analysis mark, Ugur Sahin, CEO and co-founder of BioNTech, said: “[This] indicated that a high rate of protection against COVID-19 can be achieved very fast after the first 30 microgram dose, underscoring the power of BNT162 in providing early protection… These achievements highlight the potential of mRNA as a new drug class.”
Two doses of 30 micrograms, 21 days apart, injected intramuscularly was the vaccine dose regimen used in the trials. As Sahin remarked, the results do herald the arrival of a new class of vaccines that employ synthetic mRNA platforms. It is literally a plug-and-play vaccine. For producing vaccines against any other disease, all that needs to be done is to insert the appropriate code for the antigenic protein of the other pathogen into the mRNA platform instead of the SAS-CoV-2’s S-protein code used here.
In the release the companies also stated that since the safety milestone required by the U.S. Food and Drug Administration (FDA) for Emergency Use Authorisation (which is, monitoring half the participants in the study for at least two months after the second dose) had been met, they would be submitting within days a request for the EUA based on the totality of safety and efficacy data as well as manufacturing data relating to the quality and consistency of the vaccine. The companies also said they would be submitting the same to other regulatory agencies around the world.
Two days later, on November 20, the duo submitted an application for EUA to the FDA. Based on current projections, the company hopes to produce up to 50 million doses in 2020 and up to 1.3 billion doses in 2021.
However, cautioning the FDA against rushing into the approval, Barbara Alexander, president of the Infectious Diseases Society of America (IDSA), called for a comprehensive, transparent review of data, including evidence that the vaccine has been studied in diverse populations.
In a statement issued by the IDSA, she said; “A positive recommendation from the independent scientific experts on FDA’s Vaccines and Related Biological Products Advisory Committee should be required before granting an authorisation. Any vaccine’s distribution should be informed by priorities and practices recommended by the Centres for Disease Control Advisory Committee on Immunisation Practices.”
The Pfizer-BioNTech vaccine needs to be stored at an ultracold temperature of minus 70 degrees Celsius, with a tolerance window of plus or minus 10 degrees Celsius, as part of the cold chain. Given this, as the companies attempt to reach their vaccine across nations, this would pose a major challenge, especially in low- and middle-income countries which do not, and cannot afford to, have the costly infrastructure and delivery mechanisms to ensure this.
Pfizer has, however, stated that specially designed temperature-controlled thermal shippers utilising dry ice, with GPS-enabled thermal sensors, have been developed to maintain the required temperatures and to track the location along their pre-set routes. This logistics difficulty obviously implies a near impossibility to ensure proper delivery of the Pfizer-BioNTech vaccine in countries like India.
Why does an mRNA vaccine require to be kept at such low temperatures? This is because mRNA is extremely unstable and breaks apart very easily into smaller components. That is one of the reasons why even though the concept was proven in animals in the 1990s, it was not until about 2005 that techniques for stabilising it and packaging it into small particles—either lipids or nanoparticles—were developed so that it could be delivered as a vaccine. After more than a decade the technology has achieved deployable scale reliability and the COVID-19 vaccine would be the first mRNA vaccine to be approved. However, because of its inherent thermal instability, it is likely to degrade above ultracold temperatures, notwithstanding the technological advances on that front.
The Moderna vaccine
In contrast to the Pfizer-BioNTech vaccine, Moderna has claimed that its vaccine (mRNA-1273) does not require deep-freeze storage conditions. The technology used to achieve this has not been spelt out. The company has stated that its vaccine can remain stable at standard refrigerated conditions of 2-8 degrees Celsius for up to 30 days. It can also be stored up to six months at minus 15-20 degrees Celsius, a typical freezer temperature available in most hospitals and clinics.
The same has been claimed by the Indian company Gennova, which is collaborating with the Washington-based HDT Biotech Corporation for an mRNA vaccine named HGCO19. Moderna and others with more advanced technologies that obviate the need for ultracold conditions are likely to have an edge in costing and worldwide market access as compared to Pfizer-BioNTech. But Pfizer is reportedly working on the next-generation vaccine based on non-frozen formulations that would not require such extreme low temperatures.
Moderna’s announcement on November 16 of the interim results of its Phase-3 trial with its mRNA-1273 vaccine (which showed 94.5 per cent efficacy) came following an independent analysis by the Data Safety Monitoring Board (DSMB) appointed by the U.S. National Institutes of Health (NIH). The Phase-3 study, which began on July 27, had enrolled more than 30,000 participants (aged 18 or older) in the U.S. and was conducted in association with NIAID and the Biomedical Advanced Research and Development Authority (BARDA).
The ongoing trial is a randomised placebo-controlled study, with vaccine and placebo recipients in the ratio 1:1 and the choice of vaccine dose of 100 micrograms for Phase-3 was based on Phase-1/2 trials with different dose regimens (“The quest for a COVID-19 vaccine: Promising first results”, Frontline , August 14). In the prime-boost regimen that was used, the two doses were given 28 days apart.
The Phase-3 study included more than 7,000 individuals over the age of 65 and more than 5,000 Americans under the age of 65 but with high-risk co-morbidity conditions. The latter group represented 42 per cent of the total number of -participants. Participants from communities of colour, including Hispanic, LatinX and African American, represented 37 per cent of the total study population, which is stated to be similar to the diversity of the U.S. at large.
The primary endpoint of the study is the prevention of symptomatic infection by SARS-CoV-2 with statistical criteria based on the number of COVID-19 patients observed from both the vaccinated and the placebo groups for an acceptable efficacy level. The secondary endpoints included prevention of severe COVID-19 and prevention of infection by the virus.
The interim results are based on the analysis of confirmed COVID-19 cases (in both the groups) starting two weeks following the second dose of the vaccine. The analysis found 95 cases, of which 90 were from the placebo group and five from the vaccinated group, yielding an efficacy figure of 94.5 per cent. The 95 cases, the release said, included 15 older adults (ages 65+) and 20 from diverse communities. As regards the secondary end-point, the interim analysis found 11 severe cases of COVID-19, and all the 11 cases were from the placebo group.
A review of the safety data from the study by the DSMB did not find any significant safety concern about the vaccine, the release said. The majority of the adverse events found were apparently mild or moderate in severity on which basis the vaccine has been stated to be “generally well tolerated”. All the adverse events observed, including Grade-3 side-effects, were short-lived. “Preliminary analysis suggests a broadly consistent safety and efficacy profile across all evaluated subgroups,” the Moderna release said. Of course, as more cases accrue until the final analysis is completed, the estimate for efficacy is bound to change.
Impact on elderly
Shortly before Oxford University announced the interim Phase-3 results of its vaccine AZD1222 on November 23, on November 19, the results of Phase-2 trial, which specifically looked at the vaccine’s impact in older adults, were published in The Lancet. The trial found that the vaccine elicited robust immune response in healthy adults aged 56-69 as well as in those over 70 years of age. Since the findings are significant, we take note of that before we look at the efficacy data.
In the earlier Phase-1/2 trials of this vectored-vaccine, the results of which were reported before ( Frontline , August 14), the participants were only from the age group 18-55. The trials, therefore, did not study the impact of adults. In this specific trial, the vaccine was evaluated in 560 healthy volunteers grouped into three age brackets, 18-55, 56-69 and 70+, with 160 each in the first and the second group and the remaining 240 in the 70+ group. The participants received two doses of the vaccine or a placebo (a meningococcal conjugate vaccine) as in the earlier trial. According to the published results, the participants demonstrated similar neutralising antibody titres and T-cell responses across all the three age groups and no adverse events were seen in these volunteers. The data are consistent with what was found in the earlier trials, the authors noted.
This is a significant result, particularly from the perspective of the ongoing pandemic. The data indicate that older individuals are showing a similar immune response to younger adults.
The Oxford-AstraZeneca vaccine
The Oxford vaccine AZD1222’s efficacy estimate was based on the interim results of its Phase-3 trial on 24,000 participants from diverse racial and geographical groups in the United Kingdom, Brazil and South Africa since April. The vaccine group and the placebo group were randomly assigned on a 1:1 ratio. The study found that the efficacy was 90 per cent in one dose regimen and 62 per cent in another, giving a combined efficacy of 70.4 per cent. The trials were halted in September after a participant in the U.K. developed a neurological illness. The trials were resumed following approval from the U.K. clinical trials regulator.
The above efficacy estimate is based on the interim analysis of 131 COVID-19 cases, which was the target set for the interim analysis by the researchers. The target was reached on November 4. The dose regimen used in Phase-1/2 analysis was 50 billion viral particles and the second booster dose 28 days after the first shot. Although the dose regimen used in Phase-3 has not been specifically stated in the release, presumably the same regimen was used.
Efficacy of 90 per cent was found when the participants received halved first dose (i.e., 25 billion viral particles) and second standard full dose, and when both the prime and boost vaccination were at standard full doses, the efficacy was 62 per cent. However, according to reports, higher efficacy estimate is based on a much smaller sample of only 2,800 participants. So, this figure needs to be confirmed with further analysis of data from a much larger sample size. Also, additional cases will accrue by the time of the final and future analyses. The efficacy figures will accordingly change, which will also give an indication of the duration of protection. The press release stated that no serious safety events related to the vaccine were observed.
The interim Phase-3 data builds on Phase-1/2 trial results (Frontline, August 14) which have shown that the vaccine induces strong antibody and T-cell immune responses across all age groups, including older adults as discussed above, and has a good safety profile.
Oxford and AstraZeneca have stated that they would submit the trial data to regulators in the U.K., Europe and Brazil for EUA approval. The release said that British and European Union regulators have been reviewing the trial data on a rolling basis during the trials. So, the EUA approval should happen quickly.
Meanwhile, the developers have stated that further trials are being conducted in the U.S., Kenya, Japan and India, and that they expect to have about 60,000 participants by the end of the year, which should provide additional data on efficacy and safety of the Oxford vaccine. As is known, Serum Institute of India (SII), Pune, is partnering with AstraZeneca for the conduct of trials as well its production (under the name Covishield) and Phase-3 trials in India are already under way.
Unlike Pfizer-BioNTech’s and Moderna’s mRNA vaccine, the Oxford vaccine has a significant advantage of not requiring freezing temperatures for storage and transportation, because adenovirus vectored-vaccines are quite stable and can be stored at normal fridge temperature (2-8 degrees Celsius) for long periods. And unlike the other two leading vaccine candidates, the Oxford-AstraZeneca vaccine can be produced quickly in large quantities and, because of the much simpler delivery logistics, the cost will also be significantly less.
The SII CEO Adar Poonawalla told NDTV that India would be given first priority for the delivery of the Oxford-AstraZeneca vaccine. Besides, the company has already manufactured 40 million doses of Covishield, the licenced version being manufactured at the SII, and by January it should have 100 million doses, Poonawalla said.
According to him, 90 per cent of the production will be sold to the Government of India at about Rs.250 a vaccine and the remaining 10 per cent will be sold in the open market at a slightly higher price of about Rs.1,000. “We are hoping for this emergency use licence by December-end. By January we can start rolling out [vaccines],” he stated.
Therefore, if all things go as planned, the Oxford vaccine may be ready for distribution in India by January-February 2021.