How will we know if a vaccine is safe?

It won't be long until we have the final results of phase 3 trials for the three front runners.

Dr. Harry Rakowski November 12, 2020
COVID-19 vaccine

Here are some things to keep in mind as scientists race to develop a COVID-19 vaccine. Getty

The world is currently dealing with the challenges of an almost universal surging second wave which has led to increased rates of hospitalization, deaths and major restrictions to world economies and quality of life. While this remains worrisome, mortality is much lower than before because we are better prepared and those at most risk are being better protected. We also have the mitigating benefits of social distancing, masks and effective therapies for cytokine storm and blood clotting complications. However, given that we remain far from achieving protective herd immunity, we can’t simply just hope that the virus will die out. We will continue to suffer a major social and financial burden until we achieve the end game of a safe and effective vaccine.

How do we measure vaccine success?

It is remarkable that we are on the threshold of a safe and effective vaccine in under a year, compared to the usual time frame of five years or more.

While China and Russia have rolled out vaccines prematurely before full safety data is available, this is will not happen in the U.S., Europe and Canada. Within the next month or so, we will likely have final efficacy results of phase 3 trials for the three front runners. Vaccines typically require two doses, one month apart, and then a test about a week later to measure antibodies — and in trials — killer T cell response.

There are three key metrics to watch that measure efficacy of vaccinations, effectiveness in diverse populations and far fewer new COVID-19 infections developed in the treatment group compared to the control group. 

Positive antibody rates. Is there a high percentage of people that developed neutralizing antibodies similar to what is developed by those infected with COVID-19? This infers but alone does not prove effective immunity. The positive antibody rate should be well above 50 per cent and ideally above 75 per cent.

Diversity. Are antibodies developed in all age ranges especially those over 60? And in the diversity of races who are at higher risk of complications?

Control group.  Does the unvaccinated control group develop more COVID-19 infection indicating a true benefit to those vaccinated? This takes more time to determine since there is no current challenge arm to the trials, where people vaccinated voluntarily agree to be exposed to infection to confirm immunity from infection because of successful vaccination. The U.K. is an outlier; in late October, researchers at the Imperial College of London announced plans to begin the first human challenge study of COVID-19 in January.

What is the current status of vaccine development by the 4 major players?

Pfizer announced this week that its mRNA vaccine in partnership with German partner BioNTech SE is almost 90 per cent effective in preventing infection in the immunized group — a key measure of true efficacy. The trialhas enrolled nearly 44,000 patients, nearly 39,000 of whom have received a second immunizing dose. As with most trials, half were randomly vaccinated and half were not, thus allowing for comparison of good and bad outcomes. And while the prospect of finally having a successful vaccine is exciting, the early results are yet to be peer-reviewed. 

Moderna, a U.S.-based company, is also on the verge of completing second dose inoculations in 30,000 subjects in the randomized trial of its RNA based vaccine. The study includes a diverse population including those over 65, younger people with risk factors and people of colour who are at greater risk. They will also continue to monitor for side effects for two months following treatment as well as for a lower incidence of natural infection in the treated group.

AstraZeneca is completing phase 3 trials of their Oxford-developed vaccine which uses parts of the spike protein embedded into a harmless common cold adenovirus. An immune response was generated across all age groups with low side effects in the older population.

Johnson & Johnson is using an approach similar to the Oxford study, started their phase 3 trial in late September with a goal of enrolling 60,000 participants. It was put on hold in mid October while they investigated a possible adverse event. Just a few days ago, Brazil, one of the countries participating in the trial, granted approval to resume the study.

How will we know if a vaccine is safe?

Each trial has a required Data Safety Monitoring Board (DSMB) composed of a group of experts who act independently of the sponsoring company. Having chaired such a group for a device company, there is a regular, very critical review of outcome and safety data with adjudication of adverse events. It is not uncommon to temporarily halt a drug trial for careful review of such a potential adverse outcome by either the DSMB and or a Federal regulatory body. Regulatory bodies include the FDA in the U.S., the European Medicines Agency and Health Canada. The Oxford vaccine was temporarily halted because of a neurologic complication, transverse myelitis, and after careful review received authorization to proceed in the U.K. In the U.S., the trial restarted after a further one-month delay by the FDA, indicating how carefully they take safety and their independence from the political pressure applied. Drug company CEOs have vowed to not rush development for profit over safety. Even if you don’t trust them, the lessons from huge multibillion-dollar class action settlements that were due to inappropriate shortcuts are an excellent deterrent.

When can we get immunized?

It was unrealistic to think this could easily happen before the U.S. election. As phase 3 trials are ending, about two months are needed for early follow up safety data. There have been rolling submissions to regulatory agencies to speed up their approval process which likely could then come as early as January 2021 and possibly U.K. approval for the Oxford/Astra Zeneca vaccine in late December. Each of the four major companies with candidate vaccines are producing tens of millions of doses in advance of approval to be ready to deliver vaccine very quickly as soon as regulatory approval occurs. Distribution will require coordinated logistics, since vaccines need complex refrigeration and a requisite supply of needles, syringes and trained nurses administering the vaccine as well as follow up for antibody production to determine whether the vaccine worked. Countries such as the U.S., U.K. and Germany have paid large amounts to obtain vaccines first and can likely start in early 2021 to vaccinate health care workers and high risk populations. A cascade of further vaccination for other at-risk groups will follow. Those at least risk will go last or may choose to not be vaccinated. This phased process may take six months or longer.

Dr. Harry Rakowski

Dr. Harry Rakowski

Canada has made a number of vaccine orders from leading producers with few details about where we stand in line. After a botched relationship with China and CanSino, Canada is also looking internally and has now invested $173 million in the Quebec company Medicago. They are developing plant-based bio- reactors to generate virus-like particles for a vaccine which is still in early trials. The government has negotiated for 76 million doses, enough vaccine to immunize the whole population. A number of other smaller Canadian-based candidate vaccines have also been supported to a much lesser degree.

Our vaccine availability from the leading companies is opaque and we aren’t told where we stand in line to obtain delivery. Canadian vaccine development lags by many months since the companies are in earlier phase trials with inadequate levels of early data to evaluate potential success. Thus we are unlikely to have a vaccine for initial distribution until late Q2 2021. The Parliamentary committee looking into COVID-19 procurement should shed some light on this process and is a welcome undertaking. The government’s reluctance to disclose all relevant information is shameful and Pfizer’s objection, based on publicizing proprietary information, is baseless. Trial results will be very public. I doubt we are getting such a better price than other countries that Pfizer is afraid to disclose it.

Vaccination is a global need

Most people believe that as long as COVID-19 infections are prevalent in many countries around the world, no individual country such as Canada or even the U.S. is safe from further disease burden. Assuming that 50 to 75 per cent of people in North America are vaccinated, this will leave a large segment of the population at risk for two reasons. Either because they did not agree to be vaccinated, or they did not develop sufficient antibody protection, as may be the case in 20 to 50 per cent of people who don’t achieve an adequate immune response. In addition, we don’t know if the induced immune response lasts just a few months without a booster shot, or hopefully for years as is the case with some vaccines. Some vaccines may even only work for a limited time with multiple booster shots having declining benefit or even cumulative risk.

While herd immunity may occur with 70 per cent of the population either successfully vaccinated or infected with protecting antibodies, there is the risk of ongoing waves of infection as immunity wanes and there remains worldwide pockets of disease that can spread with unrestricted travel. Thus, trying to ensure adequate worldwide vaccination is both of humanitarian concern as well as self interest.

How can Canada act responsibly?

It is a fact of life that rich countries who can afford a vaccine most likely will get it first. This inequality has always been the case and is also true for life expectancy, health care, food supply and a social safety net. The U.S. has been the most openly selfish about this under President Donald Trump whose established policy on most issues is “America first.”

The world has about 7.8 billion inhabitants and ideally we need to vaccinate at least half of them. China and Russia will look after their own populations, leaving about 6.5 billion others. There are about 5.4 billion people outside of North America and Europe. If a vaccine is estimated to cost $40 U.S. per dose and for most vaccines two doses about a month apart are initially required to likely confer immunity, the estimated cost of vaccinating 3 billion people would be $240 billion U.S. This is a daunting number that exceeds all the foreign aid distributed annually by wealthy countries.

In addition, there is the challenging logistics of refrigerated storage, needles, syringes and personnel to administer it in countries challenged by simpler tasks.

Canada, with a population of 38 million, will need to spend up to $ 1.5 billion U.S. ($2 billion Canadian) to vaccinate half the population using this cost model. Fortunately we can afford it and economically can’t afford not to do it. A made-in-Canada vaccine — if it works — will be cheaper.

How do we make sure we look after our population appropriately and in a timely way — yet have the social responsibility to help others in need according to our values and available budget? We need to help countries help themselves, change the expensive and challenging cost and the vaccine delivery model.

Here are some thoughts on how we can make vaccine access equitable:

The Serum Institute of India, the world’s largest vaccine producer, has promised to produce hundreds of millions of Oxford vaccine doses for India and the developing world. The cost will be dramatically lower than for Western countries.

COVAX is a global collaboration of most of the world’s countries and the Gates Foundation to provide equitable access to testing, treatments and vaccines particularly to developing and poor countries. Canada has pledged $220 million to support vaccination in low and middle income countries and this aid should be funnelled through COVAX.

Companies are also trying to develop an inexpensive oral vaccine. I like the approach Symvivo has taken (full disclosure: I invested in it). This is a privately held, B.C.-based company performing early trials of a novel vaccine that uses a harmless bacterium to deliver spike protein antigen to the gut lining where a good deal of immune response can be triggered. The model was developed for the delivery of immune cancer therapy and revised for COVID-19. It has the tremendous advantage of likely costing about one-tenth of other leading vaccines and is easy to produce in large quantities rapidly. It is oral, thus does not need refrigerated storage, which is a challenge in many countries such as in Africa, nor trained personnel to administer it. It may not be first to come to market, but if safe and effective can be a game changer for the needs of much of the world. It may also be vital if immunity from certain vaccines are short lived and a different vaccine model is required to maintain immunity.

The promise and the challenge

We are on the cusp of rolling out a safe and effective vaccine with at least four vaccine candidates that will soon likely be available and other interesting models in earlier development. It is a testament to how so many companies and governments could act together to overcome many, but not all traditional roadblocks and red tape. There are many safeguards for monitoring both safety and efficacy, but the shortcuts taken also slightly increase the risk. There remains a great deal of vaccine hesitancy that hopefully will be overcome by scientific data and confidence in our regulatory bodies. The process must be careful, transparent, cost effective and safe. Much remains to be learned from post-market surveillance of rarer complications as well as the natural history of the duration of benefit. I am comforted by the magnitude and speed of the achievement to date and the rigorous science in place that is so key to both discovery and ongoing surveillance. We can learn how to end this pandemic and to provide a model to manage others in the future.

Albert Einstein said that, “You can not solve a problem from the same consciousness that created it. You must learn to see the world anew.” Overcoming the effects of this pandemic will require a new view of how to integrate scientific discovery with honest discourse, fairness and a collaborative world. It might just lead to a better world.

Stay safe and take the vaccine when Dr. Fauci does.

Dr. Harry Rakowski is an academic cardiologist based in Toronto.

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