Covid-19: Potential risks of fast-tracking vaccine 

August 26, 2020

The clinical development and release of an effective vaccine against any disease is essentially mandated to go through several rigorously controlled testing processes. A vaccine candidate is first identified through pre-clinical evaluations that could involve high quality screening and selecting the proper biological antigen to invoke a defensive immune response. The pre-clinical stages are also necessary to determine approximate dose ranges and proper drug formulations such as oral tablets, drops, syrups or injections. This is also the stage in which the vaccine candidate would be first tested in laboratory animals or on human cells in the laboratory, prior to moving to the clinical stage of actual human trials.

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The subsequent clinical stages of human trials are a three-phase process. Each phase tests larger and larger groups of humans. During Phase I, small groups of human subjects, perhaps 50 or so in each group, receive the trial vaccine. It primarily assesses the safety of the vaccine in healthy people. In Phase II, the clinical study is expanded and vaccine is given to a larger group of people, maybe a few hundreds, who have the characteristics such as age and physical health, similar to those for whom the new vaccine is intended. In Phase III, the vaccine is given to thousands of people, with as broad a cross-section of people as possible, and tested for efficacy and safety. Many vaccines also undergo Phase IV formal, on-going studies after the vaccine is approved, licensed and administered to humans. All these processes are known to take years, sometimes as much as 10 years. It is a very meticulously formulated and long drawn out route to ensure the efficacy and safety of vaccines.

In the case of a COVID vaccine, we really do not have the luxury of spending years on this process. However, if one was to try and condense the timelines from years to months, it is quite obvious that it would necessarily have to entertain compromises. Currently there is a world-wide rush to find a safe and effective vaccine against Covid-19. Experts and companies claim one could be on the market in 12–18 months. The President of the United States of America wants one by the end of the year. According to the World Health Organization (WHO), a significant number of candidate vaccines are in clinical trials, with a couple already in Phase III and several others likely to enter those final stages. The plethora of COVID-19 vaccines in development gives us many attempts at getting a potentially useful vaccine. But it has to be stated clearly and unequivocally that rushed development could mean missing information about long-term safety and the levels of protection. The accelerated speed of development of the COVID vaccines has public health experts gravely concerned that vaccines might be approved with incomplete data and analysis.

This apprehension intensifies because many of the vaccine platforms in development against Covid-19 are unproven new technologies. Byram Bridle, a viral immunologist at the University of Guelph in Canada, who has received Covid-focused funding to develop a new vaccine, has said “Developing a vaccine even in about a year is unprecedented. As a scientist with expertise in the field I am personally concerned that conducting science too fast could risk compromising the rigour needed to properly assess vaccines”.

Among the top fears is the potential that a fast-tracked vaccine will have unintended side-effects. No vaccine is 100% safe, but if a billion people are vaccinated, a one in 10,000 serious adverse event will affect 100,000 of those people. In May, it was revealed that four out of 45 people in Moderna’s Phase 1 COVID vaccine trial experienced ‘medically significant’ adverse events. The most important thing is to stringently ensure that fast tracking does not mean major compromisation on safety or efficacy. Rarer adverse events need even larger trials, and as explained by Gregory Poland, Director of vaccines research at the Mayo Clinic in Minnesota, USA, ‘We won’t know about rare events until after the vaccine is licensed”.

One potential adverse event is antibody-dependent enhancement (ADE), a type of immune reaction where vaccination makes subsequent exposure to the virus more dangerous. This condition has been observed with some vaccines for the dengue virus, as well as in animal models for the original Severe Acute Respiratory Syndrome (SARS) virus. ADE occurs when the body, primed by a vaccine, generates antibodies that do not sufficiently neutralise the virus when later exposed to it and instead encourage the virus to get into cells and replicate, exacerbating the disease.

However, there is still a lot we do not know about coronaviruses, which is another concern with speedy vaccine development. For example, the question mark over immunity; are antibodies protective and how long does immunity last? Bridle says fast tracking vaccines risks compromising assessments of immunological memory. Arguably, a vaccine against Covid-19 should confer immunity for more than one year to reduce the risk of future recurrences. But how long would it take to determine if a vaccine can confer immunological memory for one year? Of course, it would take at least one year. So how does that fit into the goal of getting a vaccine into broad public use in under a year? Any vaccine is useless if it does not confer long-term immunological memory to respond when exposed to the virus.

Currently a somewhat controversial scenario has developed in the COVID vaccine development. In Phase III trials it is necessary to give the vaccine to a group of normal individuals the test vaccine and give another comparable group a placebo and all participants then have to go about their life as usual. They are all followed up for a prolonged period to see whether the vaccine protects against the disease. This will invariably take a long time. Until enough of the participants get the disease, there will not be sufficient data to draw worthwhile conclusions. To get over this requirement of prolonged observations, some people are now starting to advocate a more controversial model. Instead of waiting for any of the participants to contract the disease naturally, if at all, what if we give a set of willing volunteers in the vaccine group, the virus on purpose? These are called ‘Human Challenge Trials’. In some countries there are volunteers who have come forward to be willing to be exposed to the virus after vaccination with the trial vaccine. They have expressed various altruistic sentiments to speed up things so that the rest of humanity would benefit. Researchers had done such trials with a Typhoid Vaccine in the UK in 2016. The researchers in that trial felt that they saved three to four years of observations by that manoeuvre. In human challenge trials of a COVID vaccine, the entire process could be shortened to a matter of months.

 

However, and this is the real crux of the matter, in the human challenge trials which had been conducted for other diseases like typhoid, cholera, malaria etc, we do have effective treatments for those diseases. No one has actually died in those studies because if the vaccine was unsuccessful, they could be treated. That is where COVID-19 is in a special group. WE HAVE NO EFFECTIVE SPECIFIC TREATMENT FOR IT. If in a human challenge trial for COVID-19, the vaccine fails, there may be deaths of some of the volunteers. Such a trial in COVID-19 vaccine would be conducted in young healthy and much narrower group of people than in a conventional Phase III trial. It is to their eternal credit that these brave volunteers are prepared to take that small risk if their participation would help wider humanity. Yet for all that the risks are very real. In addition, if it works in that set of people, we will not be able to say for sure whether the vaccine will work as well in a wider cross-section of ordinary people and particularly in the elderly. Also, there are the potential prospects of some long-term effects of COVID-19, even in young people. Some authorities have labelled the human challenge trials as a ‘morally murky way’ of speeding up the COVID-19 vaccine process

Yet for all this, any risk of harm or death in a challenge study for COVID-19 would completely set it apart from all other challenge studies. Obviously, in the face of all this, many vaccine researchers would be reluctant to go into such trials for a COVID vaccine. However, the Oxford group that is doing Phase III trials on their vaccine are considering a challenge study by the end of the year. If the conventional Phase III trials that are currently being conducted find a useful vaccine, we may never have to do human challenge studies in COVID-19.

Ensuring a vaccine is safe and effective will be essential in keeping the public trust in vaccines. There is a risk that a fast-tracked vaccine could dent this and compromise vaccination programmes. Already in the US, around 30% of the public say they would reject a COVID vaccine, according to various surveys. Poland says policies have to be driven by science and effectively communicated to the public. But with economies flagging from the health crisis, will society accept more risk in a vaccine? That could be the case with Covid-19. Poland says the risk­–benefit ratio of all vaccines will be carefully reviewed by authorities but notes that risk boundaries are subjective.

To be quite fair, even a not so perfect vaccine, that could provide at least more than 50 per cent protection, could still slow the spread of the disease and save lives. But safety and efficacy concerns aside, there is more at stake here. Covid-19 will not be the only coronavirus pandemic in the future. The risk is if we do not build on the scientific gains once this pandemic recedes and if we fail to use the data and technology to be ready to develop a safe and effective vaccine for the next coronavirus or any other blight for that matter. It is obvious that the entire world would then be at grave risk in the future.