Issue #69: Vaccination, risk/benefit, herd immunity and passive immunity

Written by Nobel Laureate Professor Peter Doherty

Before taking the discussion of possible drug and antibody treatments (#66, #67, #68) further, I’ll step back to summarise where we are with protective immunity. Through this series we’ve looked at the antibody, or immunoglobulin (Ig), response (#18, #19, #20, #21) that, whether induced by vaccination (#43, #44, #45) or infection (#11, #19, #46) is our major protection against catching COVID-19 for a first (vaccines), or second (#23, #24, #25) time. As we’ve seen with the global rollout of vaccines against SARS-CoV-2, even outstanding products like the AstraZeneca adenovirus-vectored and Pfizer/BioNTech mRNA vaccines may not protect against some virus replication in the upper respiratory tract (URT). And, while people who’ve had two vaccine shots are about 90% less likely to develop severe disease that requires hospitalisation (#49)they can still transmit the delta variant of SARS-CoV-2, though likely at a lower level.

Why is there that divergence between mild infection in the URT and severe clinical consequences for those who aren’t fully vaccinated? Vaccine injected into the arm leads to the clonal expansion of virus-specific T cells and B cells in the regional lymph nodes (#42), then the localisation of (B cell-lineage) Ig-producing plasma cell ‘factories’ to the bone marrow. Here, they constantly secrete virus-specific Igs into the blood that take-out (neutralise) any SARS-CoV-2 virions that get into the circulation. Stopping (or limiting) this ‘viremic’ phase protects major organs like the heart, kidneys and brain, along with the epithelial layer of the blood vessels which, if infected, can trigger the formation of potentially lethal blood clots. On the other hand, the much lower levels of Ig that have ‘spilled over’ into nasal mucus (#10, #11) will be less likely to ‘hit-on’ an incoming SARS-CoV-2 virion before it encounters an ACE2+ positive URT epithelial cell, invades and starts to produce new infectious progeny.

What this tells us with respect to opening up Australia by achieving ‘herd immunity’ is that those who are unvaccinated cannot expect, as is the case with many other infections, that they will be safe because the vaccinated people around them have protective antibodies.  The unvaccinated can catch COVID-19 from vaccinees who are fully immune but, nonetheless, may still be breathing out some virus. We can see the consequence of that in the USA, which has around 70% of the population (aged 18 and over) fully vaccinated. As at 16 July, 2021, 99.5% of those Americans who are dying from COVID-19 are unvaccinated.

The consequence here is that the medical profession, public health officials and politicians are doing everything possible to encourage those who are hesitant re vaccination to ‘arm up’ for the appropriate product when available. It’s just a jab! Hopefully we all understand that, as with any medical procedure, there’s a risk/benefit aspect to this equation. For comparison, the possibility of dying from the rare blood clot problem associated with the AstraZeneca vaccine ranges from about 1:1,000,000 to 1:200,000, while the likelihood of being killed in (or by) a motor vehicle is about 1:25,000. For an unvaccinated 50-year old, the chance of dying from COVID-19 is about 1:500 and, of course, that goes up dramatically with age.

That leaves the question, how do we protect those who, for one reason or another, cannot be effectively vaccinated? Perhaps they are immunocompromised due to, say, treatment with a cytotoxic drug that knocks out cancer cells, but also kills their immune cells. Or, they may have some form of genetic, or age-related, immunodeficiency. Such people are normally protected by being dosed regularly with a product like Intragam® 10. This consists of about 10 grams of plasma protein obtained from the blood bank and purified commercially (from pools of 1,000 plasmas) to be about 98% IgG. What we’re talking about here is being protected by passive immunity (#5).

How does that work in practice? Products like Intragam will not normally be available to anyone who is immunocompetent, partly because of concerns that the recipient will start to make antibodies against blood proteins including Igs (anti-idiotypes) from immunologically ‘foreign’ donors. Those who are accepted for such treatment will go to a clinic, perhaps once a month, where they will need to rest for a couple of hours while these polyclonal antibodies specific for many different potential pathogens are given via a line connected to a needle in the arm.

Of course, as more and more people are vaccinated, this blood plasma will increasingly contain Igs specific for the SARS-CoV-2 spike protein. If you’re a vaccinated blood donor, don’t be concerned that any such loss of circulating antibodies might compromise your protective immunity to SARS-CoV-2. The plasma cells in your bone marrow will quickly make up any deficit. And, if you’re vaccine-hesitant, understand how fortunate you are in being able to achieve much better protection by just getting a couple of shots in the arm!

As we discussed early on (#10), the very first immunotherapy to protect against pathogens were antisera from horses that had been immunised against diphtheria toxin. Very ill patients injected with horse serum were, in the context of the medicine of that day, miraculously brought back to health as the diphtheria toxin was neutralised. While products like Intragam can potentially be used in that way, the powerful Ig therapeutics of today are the monoclonal antibodies, the marvellous mAbs (#68). Next week, we’ll embark on the tale of how the mAbs transformed both medical research and clinical medicine.