COVID-19 Vaccines : Back to normal?

Where we are with current vaccines? How do they work, and what do we know about their strengths and weaknesses? Who cares? Aren’t we saturated with news about bloody COVID-19? Why should we care?

I care. Getting the vaccines right is important. Yet in among all of the data about vaccines, I’ve struggled to find balanced, joined up information. Hence this little overview, which strangely enough ends on an upbeat note.

For your convenience, I’ve broken the body into three: vaccines that are “at the front”, “perhaps a bit dodgy” and “in the pipeline”. The most important bit may be at the end, where I answer the question “Will vaccines return us to normality?” But first, some vital, viral information. You may well be familiar with these ideas already — if so, glance through them quickly.

The spike protein, from Roger Granet’s superb CAS blog

COVID-19 vaccines demystified

What you need to know, in brief summary:

· The best target for the immune system here is likely the spike protein of the coronavirus, shown above. This protein is needed by the virus if it’s to sneak into your cells. By blocking the spike we stop the virus as it tries to colonise us.

· Several vaccines leverage novel technology that has been worked on for the last decade or so, often for other purposes like cancer vaccines.

· The mRNA vaccines use specially constructed liposomes to insert messenger RNA (mRNA) into target cells. As cells normally do, the mRNA is then used to make proteins — but these proteins are stabilised copies of the viral spike protein. Immune cells (APCs, antigen-presenting cells) now fire up the immune system, which makes antibodies to the spike, and also goads cellular immunity into vigilance.

· Viral vector vaccines are specially modified viruses that can’t breed. They provoke an immune response in two ways — through the mRNA they contain and because they have spike proteins on their surfaces. One issue here is that you can’t use a common human virus, because the body may have already been exposed, neutralising the vector without necessarily provoking a response against the spike protein.

· Conventional vaccines tend to use killed viruses, fragments of viruses, or attenuated (milder) forms of a virus. We’re a bit concerned that these won’t work for SARS-CoV-2, the virus that causes COVID-19, because you can get repeatedly infected with many other coronaviruses despite having had previous infection with these. (After his infection, Trump was likely wrong to say “I’m immune”, to the dismay of epidemiologists and virologists).

· COVAX is an international initiative that will try to co-ordinate fair distribution of vaccines. Almost everyone has joined — apart from Russia, China and (of course) the United States of America.

Phases of Clinical Trials

It’s also wise to understand the differences between the various phases of clinical trials. The terminology may vary, depending on whom you consult. Phase 0 trials are a newer idea: at the very start, a few, select patients are given tiny doses of a drug or vaccine, as a first test of safety and the body’s response. More conventional Phase I trials look at dose-ranging and initial safety concerns: again a small number of healthy people are given incremental doses, to check for tolerance. In Phase II, larger numbers of people from a broader population sample (or even those with a disease) are dosed with careful surveillance of responses to different doses, but there is often no “placebo arm”. Those doing the trial are often not ‘blinded’, so participants know that a given patient got the drug. This is one of several reasons why large Phase III trials are so critical: if you are a patient and you know you got the drug, or you are a clinician and know who received the drug, this may bias your judgement.

Phase III trials largely eliminate the problem of bias by ‘masking’ or ‘blinding’ both the recipient and the clinician, and having a substantial ‘control group’ who receive a look-alike placebo instead. Only at the end do you know whether the drug worked. In addition, Phase III trials are often — and should be — very large, so that solid numbers can be obtained. Allocation between active drug and placebo is random, to prevent another source of bias. Vaccine approval should therefore be on the basis of thorough assessment of Phase III studies.

Many approvals of coronavirus vaccines so far are emergency use approvals, without full scrutiny, an approach that carries some residual risk. In some cases, political pressure has also been brought to bear. This brings us to the matter of “Phase IV” — the most important part of every deployment of a new drug, vaccine or device is meticulous follow-up, often for years. Late problems can then be detected.

The Pfizer vaccine

At the front

Pfizer have partnered with BionNTech (and Fosun Pharma) to produce the less-than-eponymous frontrunner, BNT162b2 (tozinameran). In a large Phase III trial of about 40,000 patients, this mRNA vaccine provided 95% protection against infection in the 20,000 who received it, and on preliminary evidence appears to prevent many cases of severe infection. On 8 December 2020, the first patient in the UK received the vaccine outside of a clinical trial under emergency authority; this was followed by a mass rollout. Vaccination in Canada and the USA will follow shortly, and likely also in Bahrain, Mexico and the UAE; many others are lining up.

The down side: The vaccine must be kept at -70 Celsius until just before administration, and most countries don’t have such a well developed cold chain. The vaccine is also a bit pricey and two doses are required, about 3 weeks apart. On the first day of release two severe allergic reactions were picked up (in 40,000 cases) so more allergic (anaphylactic) reactions can be anticipated in rare cases, and the vaccine should not be given to those with a past history of severe allergy.

Moderna have completed their phase III trials of the mRNA-1273 vaccine, and will soon be ready to roll. This vaccine is also mRNA-based (as the name Moderna suggests) but it is a bit more tolerant of temperatures, although it still has to be kept sub-zero in the cold chain. It provided similar protection to Pfizer’s offering. The down side: apart from the moderately stringent cold requirements, this may be the most pricey of the vaccines. As with most of these vaccines, two doses are also required.

AstraZeneca have partnered with the University of Oxford to make a viral vector vaccine called ChAd0x1 nCoV-19 (What a mouthful! Also known as AZD1222.) In their Phase III trial, overall protection was a bit less than that of the Pfizer and Moderna vaccines — about 70%, but this is still acceptable. The vaccine is based on a chimpanzee adenovirus. A big advantage of this vaccine is its cost — about one fifth of the other two mentioned above. The Phase III trial was paused transiently owing to an apparent complication (transverse myelitis in a single patient) but then resumed without further ado.

Sputnik V vaccine

Perhaps a bit dodgy

The following vaccines have been put into service before the results of Phase III vaccine trials were concluded. This smacks of political interference and hype, so they should in my opinion be regarded with extreme caution.

Gamaleya produced the Sputnik V vaccine, where the hype has consistently led the science. The very name suggests grandiose posturing about past glories, and they have been peeking at their Phase III results for some time now, claiming over 90% success on small initial numbers. Their claims have been received with some skepticism. Quite frankly, because of the hype, even when results are released in full, I’d suggest that they should be scrutinized with extreme caution for irregularities, but even then how can we know that adverse effects weren’t simply “left out”? This is a non-replicating viral vector vaccine, with the claim that it’s better than others because two distinct viral vectors (Ad5 and Ad26) are used.

Yet another Russian-approved vaccine is EpiVacCorona, a peptide vaccine made by the Federal Budgetary Research Institution State Research Center of Virology and Biotechnology. The basis of this approval seems unclear.

Sinovac are the makers of CoronaVac, which has already been deployed in China, again without Phase III results. This is a bit embarrassing, and similar concerns apply, as with the Russian offering. This is a more conventional vaccine, made with inactivated coronavirus (formalin + alum adjuvant).

Sinopharm and the Beijing Institute of Biological Products have BBIBP-CorV, an inactivated vaccine approved for use in China and the UAE. The basis for this approval seems unclear at this time. Another vaccine approved in China doesn’t seem to have a name — it’s an inactivated vaccine co-produced between Sinopharm and the Wuhan Institute of Biological Products.

A salutary lesson comes from the vaccine that was being developed in a partnership between CSL and the University of Queensland. This innovative vaccine stabilised the spike protein using powerful ‘Molecular Clamps’ taken from HIV (without any risk of HIV, of course, as that would require a full, active virus). However preliminary results showed that the vaccine resulted in a false-positive screening test for HIV! Vaccinate the whole population, and your screening for HIV vanishes in a puff of smoke, necessitating abandonment of this otherwise promising approach.

In the pipeline

There are several other vaccines in Phase III.

Johnson & Johnson, through their intermediary Janssen, have produced JNJ-78436735, an adenovirus vector vaccine (adenovector; formerly called ‘Ad26.COV2.S’). One advantage here might be that a single dose will likely suffice. The J&J trial was paused in mid-October due to a single, serious side effect. The company has been less than totally forthcoming about this (thought to be a cerebral venous sinus thrombosis in a young person) but subsequently the trial has resumed and we are told that the problem was considered unrelated to the study drug.

Bharat Biotech make Covaxin, an inactivated vaccine still being tested.

CanSino Biologics make Ad5-nCoV, yet another adenovector vaccine.

Novavax make NVXCoV2373, a nanoparticle vaccine.

The Vector Institute make EpiVacCorona, a vaccine based on viral peptides.

There’s host of other vaccines being developed against SARS-CoV-2 — over 50 of them. Several are edging into Phase III (as of December 2020), including Inovio Pharmaceuticals’ INO-4800 (DNA plasmid vaccine), GSK/Dynavax/Medicago’s VIR-7831 (plant-based adjuvant), and Pfizer’s BNT162 (not to be confused with BNT162b2, above). You can follow progress at the RAPS vaccine tracker website, or the WHO.

We’re starting to understand transmission, but will the vaccine reduce this?

What we still don’t know

The most important unknowns are:

1. Do any of these vaccines protect against transmission? In other words, can you still harbour and transmit the virus, even though you mayn’t be ill?

2. How long will the vaccines last? It seems that they produce more durable and vigorous immune responses that, say, mild natural infection, but we still don’t know whether you need a jab every year, or every few years.

3. Are there any long-term side effects? We’ve seen very few — and generally mild — acute side effects, although two in forty thousand people had severe allergic reactions on release of BNT162b2, but will any strange side-effects pop out of the undergrowth?

The Diamond Princess cruise ship

Will vaccines “return things to normal”?

The sort answer here is “Not for the foreseeable future”. This may seem a bit disheartening, but is likely the unvarnished truth. It is almost certain that many countries will contain the virus with a concerted effort, but it is likely that poorer, less-developed countries will still see spread of the virus for some years to come. It’s quite likely that the virus will still be around, causing trouble into 2025, or even beyond. In contrast, you should note that — apart from tourism — citizens of several countries that bit the bullet early on are living pretty normal lives in Australia, New Zealand, Taiwan, Thailand, Vietnam and so on. Others are less happy.

The World population is about 7.8 billion. As of mid-December 2020, there have been 1.6 million reported deaths, and 72 million reported infections from SARS-CoV-2. Both of these are likely gross underestimates, particularly the second figure. If we assume there have been 2 million deaths so far, this likely represents at least 400 million infections (with an infection fatality rate of 0.5%). Conservatively, it seems reasonable that the number of infections and deaths will double by mid- or end-2021. If the World can vaccinate a billion people in 2021 (likely at the upper end of reasonable logistics) that will still leave six billion or so people worldwide who can become infected, with perhaps 5 million deaths per billion infected in subsequent years.

In addition, no vaccine will provide 100% protection. If you receive several doses (you may also need to be up-to-date, and receive boosters) then you will likely be at decreased risk of getting COVID-19. You may even be at decreased risk of spreading it to unprotected people. But the risk may still not be negligible. Especially if you’re older or have reason to suspect that your immune system is not healthy, you may be wise to travel less, especially to countries where control of the virus is poor. ‘Normality’ as we saw it is not an option. There are other reasons to be cautious. The virus may still reappear in countries where anti-vaccination sentiment (‘vaccine hesitancy’) is strong, even if it seems to be controlled.

One thing you might do is watch insurance companies, who are quite risk averse. When they’re offering full cover (including COVID-19 repatriation) for visits to say India and Africa, likely based on being up-to-date with vaccination and not having obvious risk factors, then you can be pretty sure that things are approaching“back to normal”. Watch the cruise ship industry, too, if it still exists.

It’s clear that the vaccine is no replacement for all of the other good measures that have been shown to work for virus control. In countries like Taiwan, New Zealand and Vietnam, sickness and death from COVID-19 has been minimal, because the government and population got on top of the virus through solid epidemiological measures. Other countries have been less robust in their approach, with devastating consequences both for their vulnerable people and their economies. The mere existence of a vaccine is clearly not a reason to relax caution — but even when it’s being deployed, lack of vigilance and failure to get the basics right would be quite silly.

All is not however gloom, as I point out in my book Rona. We can learn from the virus and find new ways to exploit the societal changes that are necessary, not just to counteract coronavirus, but to fix issues like the damage we’re doing to the planet in so many ways. We can re-examine what is really important to us, and act accordingly. We have the choice: either lapse into despair, or use our new knowledge to build a better world society.

Your call!

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Can’t sing. Can’t dance. Can program a little. Has a few medical degrees &c.

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Dr Jo

Can’t sing. Can’t dance. Can program a little. Has a few medical degrees &c.