An illustrative photograph of two vials labelled ‘COVID-19 vaccine’. Photo: Nataliya Vaitkevich.
There is euphoria following the pharmaceutical company Pfizer’s press release on November 9 that on a review of preliminary results, its vaccine candidate was found to be “more than 90% effective in preventing COVID-19” among trial participants.
The announcement was widely criticised for being misleading, while a number of other companies rushed to announce that their trial results were due shortly.
Over this clamour of claims and counterclaims, scientists have pointed out limitations in the way in which vaccine candidates are being tested, which requires a more sober appraisal. The urgent need for a vaccine against COVID-19 may lead to the use of vaccines of limited value and less than ideal information on their safety. The people must understand these constraints. They must also be assured that the vaccine will be rolled out with all the necessary precautions for follow-ups and the investigation of possible vaccine-related injuries.
For some months now, we have been following the race for a COVID-19 vaccine – the shot that will let us go back to living a normal life. This has been marked by dramatic flourishes.
One such was when the CEO of the Serum Institute of India, Adar Poonawalla, announced the manufacture of millions of doses of a number of vaccine candidates even before trials had started, so that if an effective vaccine was found, it would be available right away for distribution. Some months later, he tweeted asking the Indian government whether it was ready with Rs 80,000 crore so that all Indians could get the vaccine in the next year. All this, before the vaccine candidate has even been proven to work.
Such reports built up to a drumroll on November 9 when Pfizer issued a press release with the preliminary results of its vaccine candidate, developed along with BioNTech. The same day, WHO’s chief research officer tweeted: “The shot that rang across the world – Pfizer’s and BioNTech’s vaccine is the start of the end of the pandemic.” Shortly after Pfizer’s stocks rose by 15%. And interestingly, on the same day, its chief executive sold 62% of his stock at near-peak prices. The company also announced that it would have enough data to apply for emergency use authorisation in the US by the end of the month.
This was not surprising – only more evidence of the high financial stakes in the COVID-19 vaccine race. Indeed, a good amount of the reporting on COVID-19 vaccines consists of press releases with an eye on the market.
Now, we are given to understand that the vaccine is almost upon us, and the discussion has become focused on logistical issues, such as the need to store it at very low temperatures. And since there will be limited supplies initially, we are called upon to plan for who should get the vaccine on first.
While these questions are important, immunologists like Satyajit Rath have pointed out that we don’t yet have a vaccine. We only have a number of vaccine candidates. Dr Rath, a scientist at the National Institute of Immunology and the Indian Institute of Science Education and Research, Pune, was speaking during a webinar series on the science and ethics of COVID-19 vaccine research and access (this author moderated the second webinar). While there are 10 vaccine candidates in phase-3 clinical trials, none of them has so far released data to establish whether or not they work at all against the disease.
If and when a vaccine does become available, there are a number of issues we should address when preparing for a national COVID-19 immunisation programme.
First, the clinical trials to test the COVID-19 vaccine candidates are designed such that any vaccine that is proven to be effective will have limited value.
To sum up the process – in phase-3 vaccine trials, one group of participants is given the vaccine candidate, and the other group gets a saline solution, or placebo. Neither participant nor investigator knows who got which. Both groups are then monitored to see if they develop the disease that the vaccine candidate is designed to prevent. The number of cases of disease in each group will be compared to evaluate the efficacy of the vaccine. For the vaccine candidate to be judged efficacious, the control arm should have a greater proportion of cases. Researchers perform an efficacy analysis after a predetermined number of cases have been recorded. Final efficacy analyses in COVID-19 vaccine trials typically require 150-160 cases.
Peter Doshi, an assistant professor of pharmaceutical health services at the University of Maryland and associate editor at the BMJ1, has argued that the phase-3 COVID-19 vaccine trials are not designed to test for what we need to know – whether the vaccine candidate will prevent severe disease. He pointed out that the primary outcome for these vaccine trials is simply a laboratory-confirmed case of infection with SARS-CoV2, with at least one symptom – which could be as mild as a cough, fever or diarrhoea.
In Prof Doshi’s testimony to a US Food and Drug Administration (FDA) committee on the COVID-19 vaccine, he said that the vaccine candidates should be tested for how well they prevent severe illness leading to hospitalisation, ICU stay or death. The trials either don’t measure this or they are not set up to measure it well. In fact, the researchers stop the trials when they meet their target of 150-160 cases.
In order to evaluate efficacy against severe disease, these cases need to include sufficient numbers of severe disease, which is unlikely to happen, as severe disease is much less common than mild forms of the disease. The trials are also not designed to measure whether they reduce illness in those at greater risk, such as the elderly, or those with comorbidities. And they don’t collect the information needed to know if the vaccine could reduce transmission of the disease to bring the pandemic under control.
Dr Rath also agreed that the trial designs have these limitations. “I would like trials to do both – give substantial protection against severe COVID-19 as one component, and cause an enormous reduction in the quantity and time of excretion of the virus if infected” to reduce the chances of infecting others – but he also holds that they will still provide sufficient useful information.
“The current efficacy endpoints take an in-between position of looking for reduction in symptomatic infection,” he added. It can be reasonably expected that if a trial establishes the vaccine candidate’s efficacy, the vaccine should reduce both severe and mild illness. “This vaccine is expected to provide some protection at the individual level, and some at the community level.”
A second concern is the bar set for efficacy. The WHO recommends that a vaccine be at least 50% effective (range 30-70%), and the FDA requires this minimum as well. The WHO expert group on COVID-19 vaccines states that while a higher level would be desirable, a vaccine of at least 30% efficacy – if used on a large scale – could help reach population immunity. However, for the individual, such a vaccine might be of limited personal benefit, especially if it is shown to protect only against mild forms of the disease.
A third concern is that because of the urgent need for a vaccine against COVID-19, a vaccine meeting these standards will get emergency use approval immediately, with limited information on safety. “Such a short duration for adverse events monitoring is not good,” Dr Rath noted in the webinar, adding, however, that “this may not be a major concern preventing provisional or emergency use regulatory approvals for an efficacious vaccine.”
But Peter Doshi views this differently. In a commentary, he and Eric Topol, another vocal critic of the COVID-19 vaccine trials, wrote, “stopping a trial of 30,000 or 44,000 people after just 150 or so COVID-19 cases may make statistical sense, but it defies common sense. Giving a vaccine to hundreds of millions of healthy people based on such limited data requires a real leap of faith.”
Some side-effects may be identified only after millions of people have received the vaccine.
Such doubts are relevant when rolling out an immunisation programme to millions of Indians. So before we discuss who gets a COVID-19 vaccine on priority, we must ensure transparency on all aspects of the vaccine – the objectives of the vaccine programme, how the approved vaccines measure up to those objectives, and how to ensure long-term follow-up for serious side-effects.
The public should understand a vaccine given in sufficient numbers is expected to cut down transmission and bring the pandemic under control, but will guarantee only moderate protection, and only against mild disease. “In the media and ordinary discourse, they are talking about individual protection,” says Dr Rath.
Second, the public must be assured that those running the immunisation programme will conduct long-term follow-ups for possible vaccine-related injuries. For this, we need to strengthen the existing Adverse Events Following Immunisation (AEFI) Surveillance programme.
The authorities should be open, honest and scientific in their actions and public communications. By eliciting the public’s voluntary cooperation, the authorities may be able to tackle the disease effectively. On the other hand, opacity on the vaccine’s benefits and limitations will lead to suspicion of vaccines and could harm the cause of public health.
Sandhya Srinivasan is a Mumbai-based freelance journalist and researcher. She is a consulting editor at the Indian Journal of Medical Ethics.
Formerly the British Medical Journal↩