Mumbai: Several drug makers have announced that they are moving on to expanded phase II clinical trials for a vaccine for COVID-19. Phase II usually involves a larger pool of candidates, and focus groups of children and the elderly. Some 165 vaccines are now being developed worldwide, and about 12 candidates are believed to be in phase II globally. A few others have started phase III as well, like the vaccine from Oxford University.

What does this mean? When we go into such trials, does this mean a vaccine is around the corner? What should people who are likely--or wanting--to take them expect? What should they be careful of, particularly as we are at an early stage of research?

We speak with S.P Kalantri, director and professor of medicine at the Mahatma Gandhi Institute of Medical Sciences and medical superintendent of Kasturba College, Sevagram, Maharashtra, and N. Kumarasamy, chief and director, Infectious Diseases Medical Centre at the Voluntary Health Services Hospital, Chennai.

Edited excerpts:

Dr Kalantri, where do we stand in these clinical trials? As lay consumers and audiences, what should we be reading into them?

SPK: I am reminded of a famous quote about British weather, that the only certainty in British weather is its glorious uncertainty. I guess the same holds true for this virus also. Nobody knows how it is going to behave, nobody can predict its future. Even the virus does not know how it is going to behave. So all our predictions, future projections, are very uncertain. The virus is very unpredictable. And honestly speaking, I do not know what the future holds for us.

Dr Kumarasamy, what is your reading of where we are in clinical trials? Are you or your organisations involved in any?

NK: I am from both the clinical unit that takes care of COVID patients and ]part of the team that conducts] clinical trials both on COVID patients and on COVID-negative people to prevent various diseases. For any vaccine for a target discovery or validation, from pre-clinical stage to manufacturing, development and clinical assay optimisation, it takes anywhere from three to eight years in a normal scenario. On the other hand, we are in a huge pandemic. Things are very accelerated, and some of the processes are truncated. That may be good and bad: You may get a product soon, but you may even bypass some stages, which may hurt some individuals if not properly carried out.

Usually, we do phase I safety study in a very small group of people. And we go into phase II, where we do study both for the safety and immunogenicity--whether this vaccine will protect you against particular organisms. And only in phase III will we test efficacy and also safety on a large number of people against a comparator arm, [which comprises trial subjects usually administered] a placebo. All this usually takes anything from two to 10 years. I was involved in several other vaccine development clinical trials in the past starting from HPV [human papillomavirus], and some TB [tuberculosis] vaccine candidates. This is the usual process, but some of the process can be fast-forwarded and truncated but not always in an ideal scenario.

There are several candidates now; people are in a race. More than 140 COVID-19 vaccines are already in the preclinical stage. Almost 19 are now in phase I trials. This is huge, in six months of time. I have never seen in any other infectious disease that so many candidates come so quickly into phase I. Also, 12 are already in phase II--that is remarkable. In this pandemic, this is really needed. And almost five are in phase III. But we need to do this in a very systematic and ethical way, so that it can be applied in very large masses without causing major issues to COVID-negative people in the process of preventing this disease.

Dr Kalantri, at this point, as someone who is on the frontlines of medicine, do you get a sense that the effort that we are putting in will be more rewarded in the form of a cure or in the form of a vaccine--while all efforts will be ongoing at any point?

SPK: I guess both things are important--prevention as well as cure. Primary prevention is important--we require vaccines to ensure that healthy individuals do not fall sick. And when these individuals fall sick and get admitted to hospital, we also need novel drugs to make sure that we do not lose them or we keep them off our hospitals as well. But as has repeatedly been said and one of the editorials in The New England Journal of Medicine put very beautifully, normally a vaccine gets about six to 10 years, but thanks to the tremendous efforts by the scientific community, researchers, virologists, public health people, World Health Organization (WHO) and by nations, we have been able to collapse this six years into six months, which is a remarkable achievement.

But I would urge a note of caution. We are past phase I and phase II, [and] the initial results look quite promising: Probably the vaccines are safe, probably they are able to mount an immunogenic effect there. But the real test of the vaccine would lie in phase III trials when hundreds and thousands of individuals and healthy volunteers participate in this study, and then we will try to find out whether the vaccine is really safe, really beneficial, [and] what is its protective effect. It might take about six to nine months or a year before the phase III studies are completed and we start getting a clearer picture as to where we are. But right now, I would again urge a note of caution. Speed is of essence, but while we are speeding, we should not lose sight of science and ethics as well.

Dr Kumarasamy, if I was asking this question as a lay person, how do I feel confident that the effort that is being put in and the standards that are being used in clinical trials are consistent across the world--including in our own country, where many drug makers are saying that they have gone into phase II?

NK: It is a very challenging question. Usually, in vaccine development, the preclinical and phase I [studies] are done by the industry in a small group of people to understand the safety in healthy volunteers. Phase II and phase III are done by academic bodies--like the National Institutes of Health in the USA, the ANRS in France, Medical Research Council in the UK, or the Indian Council of Medical Research--so that there will not be any confounders, where you are not biased towards your product. These bodies usually do [the trials] in a multi-site way.

These academic bodies select investigators who are capable of leading these clinical trials. [They] make sure that all processes [are followed]--starting from obtaining appropriate reviews from the ethics committee, approaching the needy population, recruiting with informed consent after explaining everything--risks, harms, benefits and the need for follow-up--doing all blood tests, conducting clinical trials in a highly ethical manner with a team of staff (not one individual alone), collecting the data in a professional way without any bias, tampering or malpractice, and also reporting all adverse events and serious adverse events--starting from pain, itching, swelling or even serious things like anaphylaxis-like [reaction], where someone can faint while you are giving the vaccine.

Would we be right in assuming that at this point there is no reaction at all, because we are not hearing anything? Or is it that we are not being told at this point?

NK: There are two types of reactions--adverse events and serious adverse events. The adverse events have a classification--we have grades 1, 2, 3 and 4. Usually, anything more than grade 2 is very severe, where you may have to stop administering the product and enter the person into the standard of care. Grades 1 and 2, sometimes we allow them if it is not serious, and not progressing to grade 3.

To your question, everything will have some type of adverse events. If it is an oral tablet, [there may be] nausea, vomiting, stomach pain or itching. If it is an injection, everybody will complain of pain. Some can have a little swelling. And some vaccines can produce a fever after two or three days. In a vaccine trial, we report all those. We will never say that there is no adverse event at all. The regulators look into these adverse events--whether it is related to the vaccine, or is a general process, or is life-threatening, and [weigh it against] the benefit.

Dr Kalantri, going by the information we have so far on the clinical trials being conducted--and as we have all seen now, we seem to be galloping ahead--what is your sense? Things are moving fast and vaccines are going to hit the market, and there is going to be a lot of publicity.

SPK: I think it's extremely important for the scientific community to adhere to the highest principles of both science as well as ethics, and not [let] those political forces and cheap popularity and the pressure from the media etc. be the driving force. Phase III is going to be extremely crucial, because this is the phase when you are going to enroll hundreds and thousands of participants. The volunteers do not know right now whether they will really benefit from this vaccine, but probably they feel that if this vaccine turns out to be successful, it might help the future generations. So they have probably volunteered for these clinical trials for a very altruistic reason, and we need to acknowledge that.

But it would be extremely crucial to capture and record almost every adverse event. This could be a small fever, pain, swelling, giddiness or skin rashes, or serious complications as well. Because right now, we do not know whether this vaccine is really safe, effective, how much its protective effect is. And if past experience of vaccines is anything to go by, we do know that certain vaccines were found to have very delayed but very serious toxicity. There were a few controversies as well--for example, certain vaccines have been associated with autism; the rotavirus vaccine in India was associated with a peculiar intestinal obstruction in some kids. Unless we capture these adverse events and establish a cause-effect relationship between the vaccine and these adverse events, it will be very premature to celebrate victory and break into victory dance. So I would always say that while it is important that speed is of essence, please do ensure that you make haste slowly.

Let me ask you this question a little more medically. Going by what you have seen of this disease so far, and it has been more than four months now since you have been actively working with it and around it, what is your sense? Whatever the literature you have seen on vaccines, does it look like we could potentially fight this?

SPK: It is quite possible, but my honest answer is that I do not know, because the virus is unknown. We do not know whether the virus would mutate, whether there would be cross-reactivity, and how our own immune system responds to the vaccines. Right now, these are all conjectures, and probably over the next few months or so or by early 2021, we should be able to figure out exactly where we stand. Right now, the situation is very fluid.

Dr Kumarasamy, you have worked on infectious diseases for a while and as you have said, you have also worked with clinical trials for vaccines elsewhere. So what is your sense of what the likelihood of its efficacy is, if you were to look at it somewhat dispassionately?

NK: We have different types of vaccines: DNA-driven vaccines, RNA vaccines, and certain protein-based vaccines. [Each of these] does different things. We use vectors to give [the vaccine] to individuals [in order] to stimulate the response. It can be a viral vector that is non-replicating, or a viral vector that can be replicating--we have to be very careful, as this can sometimes also cause disease. Another [type] is [where] we give an inactivated virus. Each one will have a different efficacy. But all these finally do the same thing--they stimulate the immune response to protect against the disease.

With the currently available scientific data--which is documented, peer-reviewed by researchers and has been accepted--two vaccines are really in an advanced stage. One is the mRNA vaccine developed by Moderna in collaboration with the US National Institutes of Health, which is in advanced clinical trials. They have already started phase III, which has shown a really good response. We need to wait for it. But again Anthony Fauci, who leads the NIH [National Institutes of Health, USA] efforts, very clearly says that [we have to] wait upto early 2021. It is too early to speculate but that has really gone into the very advanced stage of the study.

Another vaccine is the one by the Oxford group, which is what we call chimp-adeno Oxford 1 virus. It is now in phase III, and an Indian company, the Serum Institute, is partnering with them. It is a chimeric adenovirus vector developed by the Oxford group. It has gone into good clinical trials, and they have also shown that all the adverse events [are] not very significant to disrupt [the trial], [are] mild to moderate, which people can adjust to. It has shown a lot of immunogenicity.

We need to wait for the results and these are all very robust groups--the NIH and Oxford. They do studies in a very ethical and systematic way involving proper design. I think we need to wait for these results in a very optimistic way.

Dr Kalantri, how do you read what Dr Kumarasamy is saying? And secondly, we were supposed to be targeting a launch for a vaccine on August 15, which may not happen, but that is how we were approaching the issue. So what is your advice to those who will be watching this or reading this later?

SPK: I think it is important to go by real research. I am reminded of some statements by Dr Soumya Swaminathan [chief scientist at the WHO] as well as Dr Fauci who said that we might see the birth of this vaccine by the winter of 2020 or probably the summer of 2021, provided we are extremely lucky. I think that is very important for us to understand--the virus development is going on by leaps and bounds, but it would be very premature to [say] whether the vaccine will really be available in the next couple of months or not. So we need to wait, we need to have a lot of patience, and maybe God-willing, probably early 2021 might see this vaccine.

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