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Covid vaccines: Hope balanced with caution

COMMENT

As Covid-19 vaccine announcements ramp up, there is reason to be optimistic. But if there is one thing worse than no vaccine, it’s a botched vaccine.

Add to that a pandemic-scale disinformation campaign fuelled largely by the social media echo chamber and it is clear that there is still a lot of work to do.

The breakthrough: messenger RNA

First, on the positive side: two candidate vaccines from Moderna and Pfizer are a breakthrough technology using messenger RNA. It is worth a brief explainer on why this matters.

The classic approach to creating a vaccine is to use an attenuated form of virus – one that is damaged in some way that inactivates it – or it is based on a less virulent but related disease.

These two new designs use a wholly new idea: triggering the cell’s protein-building machinery to make a protein similar to that on the surface of the virus. It is this protein that triggers the body’s immune system. To do this, the vaccines use messenger RNA (mRNA), the chemical structure that the body uses to convey protein coding information from DNA in the cell nucleus to the cell’s protein manufacturing machinery. 

The process works broadly like this (I am leaving out a lot of detail). DNA contains a sequence that is a code for creating a protein. This is copied off through a process called transcription onto a sequence of RNA called pre-mRNA. This RNA has parts that will eventually code for protein, called exons, and other parts that are removed before the protein can be made, called introns. To cut a long story short, mRNA is a template for building a protein.

If you know the sequence of amino acids in a protein, you can reverse-engineer mRNA that encodes the protein sequence. This is what these vaccines draw on.

The basic idea of these new vaccines is to short-circuit the processes that create the virus’s own protein without the risk of something that looks like a virus being introduced into your system. Because mRNA only interacts with the protein mechanism of the cell, there is less risk of damage to DNA than with some other types of vaccine.

This sounds pretty exciting but it is too early for the approach to either vaccine to be evaluated in detail. A September 2020 paper in Nature describes the science behind the Pfizer vaccine but a process this complex will take time to be studied by other labs with the expertise to find flaws. So far, clinical trials have been promising, with effectiveness estimated at over 90% and no significant reports of adverse effects. However, I would be more comfortable with a radically new approach if independent researchers had evaluated it comprehensively.

How is effectiveness estimated? 

In a clinical trial where half the participants are treated with the candidate vaccine and half with a placebo, you expect that – assuming there is no bias in the split between the two groups – the same number in each group would contract the disease if the vaccine has no effect. If 100 of the placebo group are infected and only 5 of the vaccine group are, the assumption is that 100 of the latter group should have been infected, so the vaccine worked 95% of the time. The bigger the study, the more accurate the assumption. It helps when testing a vaccine when a disease is spreading fast; this is one reason that vaccine development for earlier deadly coronaviruses, severe acute respiratory syndrome (Sars) and Middle East respiratory syndrome (MERS), stalled. The disease was stopped before prevalence was high enough for effective trials.

What obstacles are there to large-scale deployment?

Manufacturing and deploying at scale is always more difficult than on the scale of a trial. mRNA is relatively fragile and needs very low-temperature storage to keep it stable – an issue especially for Pfizer, whose vaccine needs to be stored at an exceptionally cold -70° C. Moderna’s vaccine is stable at a balmy -20°C. The Oxford-AstraZeneca vaccine, made using a different approach, doesn’t need super-lower temperatures (an ordinary fridge will do) so that may make this or one of the other candidates a better approach for less developed countries.

Once manufacturing is organised, distribution and administering on a bigger scale than ever before will be challenging.

All of this is happening far faster than any previous novel vaccine design. Even the flu vaccine, which has to be redesigned every year for new strains, takes around 6 months to develop and deliver, despite many years of experience. Novel vaccines usually take years or even decades to develop; work on HIV vaccines has been going on since the 1980s. Some of the speed is because of new ideas that have been in the works for years; the rest is because generous funding has made it possible to avoid waiting to evaluate each step before funding the next.

A review of a ‘botched’ vaccine 

As the US shows signs of careening past 200 000 cases per day with no end in sight and with increasing numbers of states facing hospitalisation crises, there is enormous pressure to deliver on a vaccine so it is instructive to review a botched but ultimately successful vaccine.

Jonas Salk in 1955 launched the first polio vaccine, based on polio virus killed with formaldehyde. The vaccine was shown to be highly effective in massive trials but the eagerness to wipe out polio led to more than 200 000 doses being delivered in which the virus was not killed, resulting in 40 000 infections. 

The rush to manufacture was the problem, not the design of the vaccine. However this terrible failure led to the replacement in 1960 of Salk’s design by that of his rival Albert Sabin, based on live virus – but a less virulent strain. Yet Salk’s design is the superior one, less likely to result in infection, provided it’s manufactured correctly.

Today, polio is no longer the dreaded disease it used to be and only persists in a few isolated parts of the world where vaccination is inhibited by local conflicts. Ironically, the biggest cause of polio infections in recent years is Sabin vaccines where the virus was not sufficiently deactivated. Had Salk’s early vaccination programme not been marred by faulty manufacturing, polio could have been eradicated sooner and more safely.

Partly as a result of the bad experience with polio, vaccination programmes these days have numerous safeguards. Despite the enormous pressure to roll out a Covid-19 vaccine, we should not throw any of this experience out of the window. Particularly with radically new approaches, we need to be extra cautious.

But if the new mRNA approach works, it holds out promise for safe, effective vaccines for many other viruses.

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Philip Machanick
Philip Machanick is an associate professor of computer science at Rhodes University

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