A scientist dilutes samples during R&D for a COVID-19 vaccine at a laboratory in Saint Petersburg, Russia, June 2020. Photo: Reuters/Anton Vaganov/File Photo.
Late last week, Russia’s health ministry announced the findings of phase 1/2 trials of the country’s COVID-19 vaccine via a paper in The Lancet. Although not the first early phase vaccine trial to be published, the results have been highly anticipated as they form the basis for Russia’s controversial regulatory approval for this so-called ‘Sputnik V’ vaccine. In this study, researchers at the Gamaleya Institute of the ministry administered two components of their vaccine to a group of healthy adult volunteers to determine its ability to provoke an immune response, and its safety. These components were both variants of an adenovirus (commonly associated with respiratory tract infections in humans), genetically modified to carry the gene corresponding to the SARS-CoV-2 virus’s spike glycoprotein.
Using these components, Russian researchers developed two formulations of the vaccine, which they evaluated separately, in 38 patients each. This was designed as a hybrid phase 1/2 study. In phase 1, patients in both arms of the trial – all 76 – received either component intramuscularly and were evaluated for safety over 28 days. In phase 2, with 20 of 38 patients in each arm of the trial who received one of the components was administered the other component on day 21 as a booster.
The researchers reported that the vaccine was safe. Volunteers had local (at the site of injection) and systemic (generalised) side effects such as pain, fever and headache, but most of which were mild. They also noted that the vaccine components could provoke an immune response. Some 84-89% of participants had demonstrable antibodies against SARS-CoV-2 in their blood by day 14 and 100% by day 21. The booster dose on day 21 was noted to significantly increase antibody levels a week after administration. The researchers also reported that those who received both components of the vaccine had more robust antibody levels than those who received just one of them. They also showed that antibody levels against the spike protein in those receiving vaccination were comparable to anti-SARS-CoV-2 antibodies in Russian patients who had been (naturally) infected with COVID-19 and recovered.
Objectively, the trial was a success. It proved that the Russian vaccine was safe and effective – in theory. Phase 1/2 vaccine trials are designed to demonstrate safety and proof of an immune response to vaccine components in small and very healthy populations, essentially society’s ‘marathon runners’. These participants were not exposed to the novel coronavirus, so it’s impossible to know if the vaccine actually prevents infection. This information is obtained from pre-clinical data – typically by vaccinating non-human primates and exposing them to the virus. This the authors of the study have alluded to but have chosen not to publish.
In phase 3 trials, researchers rigorously test thousands of patients, often including older people who may not be as fit, and who receive the vaccine and face the risk of infection, thus reflecting how effective and safe the vaccine might be in a real-world scenario. This is why Russia’s decision to approve the Sputnik V vaccine before phase 3 trials has been met with significant concern.
This said, the results that have been republished are not without merit. This study represents another successful independent effort that used the SARS-CoV-2 spike glycoprotein to induce an immune response (like the Oxford, Moderna and Novavax vaccines have). This is arguably the approach most likely to succeed. Additionally, the Russian team showed that a booster dose improved the antibody levels and that they were sustained at 42 days. This is crucial. A small study from China had showed in June that antibody levels in up to 40% of asymptomatic patients of COVID-19 had dropped drastically eight weeks after having been released into the blood, indicating that they may be susceptible to reinfection and even that vaccination may not work as intended. However, an Icelandic study published earlier this week showed that around 90% of some 1,800 patients who had recovered from COVID-19 had demonstrable levels of antibodies for over two months after infection.
Although it will be impossible to know how effective and safe each vaccine is without well-designed phase 3 trials with thousands of patients, it seems more likely that we will soon have a number of vaccines to choose from. Of course, it remains imperative to understand what each of them does or doesn’t do. Preventing severe COVID-19 disease or death, reducing transmission rate and protecting of the vulnerable population are all scientifically and clinically valid objectives – but they are also very heterogenous endpoints. No single trial or vaccine should attempt to achieve all of these goals at once. Instead, it is likely that the more successful vaccines will achieve some of these goals; which one should be priorities already varies from one region to the next.
More broadly, based on the number of cases, healthcare capacity, death rate and transmission rate in different countries, a vaccine’s ‘success’ can’t be a static, standardised metric. At this point of time in India, with a large young population, a relatively lower death rate and low healthcare capacity, reducing the virus’s transmission rate might be more important than protecting the vulnerable population. So a more effective vaccine with a lower safety profile could be a calculated risk worth taking. However the same vaccine in an ageing Western population could be devastating.
For vaccines to work, we need to understand how we need them to work. The only advantage of there being time before we have access to multiple vaccines is that policymakers in each country can engage in transparent dialogue with experts and the people to get a sense of the realistic expectations before rolling out potentially a billion doses. They should also reach out to vaccine manufacturers to ensure the studies that are underway use the endpoint that the state foresees to be the most valuable for its population, and that trials are ethnically and racially representative as well.
In reassuring vaccine manufacturers staking significant amounts of money and their reputation on developing vaccines, policymakers should aim to foster collaboration. Trial-regulating bodies and scientific journals have a duty to ensure clinical trials are run in a scientifically sound and meaningful way, with discrete, objective endpoints, so the data can be accurately interpreted. Permitting vague objectives, subjective interpretation of results and watered-down science in major trials to procure approval for pharmaceutical and non-pharmaceutical COVID-19 therapies will only undermine public trust, such that even if a ‘good’ vaccine comes along, it may not find acceptance As things stand, the race to a COVID-19 vaccine is not likely to be a zero-sum game. The sooner we understand this, the more likely we are to succeed.
Dr Narayana Subramaniam is a head and neck surgical oncologist at the Mazumdar Shaw Medical Centre, Bengaluru.