Saturday, September 12, 2020

Coronavirus vaccines: ready for prime time?

When will we have a vaccine? Can life get back to normal when we have a vaccine? Questions like this have been in the news almost daily. The underlying questions of most interest to the public can be expressed as “when will a safe and effective vaccine be available to me and my family?” and “will the availability of a vaccine allow normal life to resume?”

Vaccine availability will not fail for lack of trying! Vaccine development is usually a back-page issue, and not a high priority to the pharmaceutical industry because profits from sale of vaccines lag well behind those of most pharmaceutical products. With the world’s attention so focused, we now have 38 vaccines against Covid-19 in clinical trials in humans and another 90+ that are in animal trials.

If you are a regular reader of these posts, you know that I consider vaccines to be the most important public health development in medical history. Prevention is always better than treatment, and vaccines have saved many millions of lives over the 225 years since Jenner’s first experiment.
What may be confusing to many is the different approaches that different researchers and companies are taking to making vaccines. Traditionally, vaccination has taken one of two forms: give people a mild illness that is close enough to a serious one that they build up their immunity to the serious one – Jenner’s approach in 1796 – or inject people with killed virus or virus particles that also lead to an immune response without getting sick – the standard approach with influenza vaccines. A major problem with the latter approach is that it is very slow, growing virus in egg cultures before destroying the virus and using it to make vaccines.

Current vaccination research is much more “cutting edge.” Genetic engineering techniques are being used; “viral vectors” are being tested: putting bits of Covid-19 RNA into harmless adenoviruses which infect human cells and produce an antibody response; getting various Covid proteins, including the spike protein, into such vectors. The many approaches taken reflect our inability to know which is most likely to work (as well as companies’ need to have their own unique product!).

As to the “when,” the issue is not developing a candidate but proving that it is both effective and safe. An effective vaccine not only results in recipients developing antibodies, which is easy to measure, but prevents disease in exposed individuals, which is much harder. There is still much we do not know about the body’s response to Covid-19; a clear worry is that people can get repeated colds, many of which are caused by other coronaviruses, so it is not clear that exposure always results in immunity. In my practice, I observed that first or second year teachers seemed to be sick all winter, but that veteran teachers rarely got colds. Perhaps we need repeated exposures to coronaviruses before our immune system can fight them off?

While vaccines in general are very safe (please don’t get me started on the “anti-vax” movement!), vaccines developed and deployed too quickly have been problematic. This can reflect poor manufacturing practices: in the 1950’s a polio vaccine manufactured by Cutter Labs intended to contain inactivated polio virus mistakenly had some batches with live virus.

In the late 1990’s the FDA halted use of a vaccine against rotavirus, a potentially fatal diarrheal illness of children, when it appeared to cause bowel obstruction, and it was eight years before a safe rotavirus vaccine was approved. The complication was rare, and so was only found after the vaccine was in widespread use.

Rushing a vaccine into use is a serious risk. Faced with predictions of a swine flu pandemic in 1976, President Ford launched a huge effort to develop and distribute a vaccine against swine flu, but the flu was less serious than predicted and some 450 people who got the vaccine developed a rare form of paralysis.

How do you develop and test a vaccine to be sure it is both effective and safe? You do not cut corners!

The first step is testing in laboratories, first in cells and then in animals. Initial human testing, Phase 1, is done in small numbers of healthy volunteers to be sure the vaccine results in an immune response and does not have obvious safety issues. In larger, Phase 2 trials, the vaccine is given to hundreds of people, generally including both children, young adults and the elderly, to see if it acts differently in different groups and to watch for obvious safety issues. If these small samples do not raise any concerns, the vaccine moves into Phase 3, in which thousands of volunteers are given either the vaccine or a placebo. These trials must show that many fewer people receiving the vaccine get sick than do those given placebo. They are also watched carefully for any less common side effects that did not appear in the early phase trials.

Only when the results of Phase 3 trials show that a vaccine is both effective and safe should it be approved. The vaccines developed in China and Russia that were rushed into production without results of Phase 3 trials may have serious risks and/or may not work.

My big worry is that a beleaguered FDA, which we have already seen respond to political pressure and approve hydroxychloroquine for Covid-19 only to later rescind that approval, will bow to political pressure and approve a coronavirus vaccine before Phase 3 trials have been completed. Hopefully the manufacturers, wary of lawsuits, will be the regulating force that our regulators should be.

A truly effective and safe Covid-19 vaccine is badly needed and will be welcomed, but “warp speed” is better left to the ships of Star Trek than to public health.

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