Scientifically Speaking | Investigating immunity levels from Covid-19 vaccines

Having biomarkers that correlate with vaccine effectiveness will allow researchers to check if immunity declines over time in vaccinated populations. It will also allow some people to be prioritised for booster shots, without the need to offer precious extra doses to others who do not need them

Imagine that it is 2022. Having received two doses of a Covid-19 vaccine a year ago, you are sitting in a doctor’s office waiting for a blood test to check how much immune protection you have against Sars-CoV-2.

Representational image. (HT PHOTO)

Creating a test that estimates the amount of immunity requires having what immunologists call correlates of immune protection — biomarkers that serve as measures of the ability to prevent infection or symptomatic Covid-19.

Having biomarkers that correlate with vaccine effectiveness will allow researchers to check if immunity declines over time in vaccinated populations. It will also allow some people to be prioritised for booster shots, without the need to offer precious extra doses to others who do not need them.

The frontrunners for such biomarkers are specific antibodies that the body generates after vaccination or after clearing the virus after natural infection. High levels of these neutralising antibodies give us the clearest path to determining the “strength” of immunity.

Correlates of protection also help in predicting the effectiveness of approved vaccines against new variants without the need for full-fledged efficacy trials. It lets researchers rapidly determine if candidate vaccines show promise by comparing them to already approved vaccines.

Over a year into the pandemic, we know that running large-scale efficacy trials takes time. Covaxin reported phase III trial results more than six months after emergency approval. A smaller phase III trial with immune responses correlated to efficacy will be useful in approving future vaccines instead of costly and time-consuming field trials.

Now, there are multiple lines of evidence that neutralising antibodies that bind to the spike protein of Sars-CoV-2 and specifically the receptor-binding domain part of it correlate with immunity. These studies also provide the first range of antibody concentrations that might provide reasonable protection with vaccines. There are neutralising antibodies levels above which vaccines are effective.

A two-dose vaccine helps maintain a high level of neutralising antibodies. Research has shown that a third dose of the same vaccine may help to boost antibody levels to earlier amounts, should the need arise. Currently, a third dose is not advised for any of the variants (except in rare cases of those who have weak immune responses due to solid tumours).

Three different approaches point to neutralising antibody levels correlating with immune protection. One approach published in Nature Medicine on May 17 by Triccas and colleagues, plotted a mathematical correlation between the amount of neutralising antibodies and the reported vaccine efficacy from clinical trials.

Moderna, Pfizer, and Novavax elicited the strongest antibody responses and the most protection, while AstraZeneca and Johnson & Johnson generated weaker antibody responses and less protection. The researchers predicted from neutralising antibody levels that Covaxin might demonstrate an efficacy of around 80%. This turned out to be quite accurate since an efficacy of 78% from phase III trials was reported on July 3.

A second approach is to conduct experiments on non-human primates. An advantage of this approach is that these animals are biologically similar to humans and can be “challenged” with a high-dose of Sara-CoV-2 to test for levels of protection after vaccination, something which is considered unethical to do in humans.

A preprint posted on BioRxiv on April 23 by Barney Graham’s team found that spike-protein-specific antibodies are correlates of protection in primates. The levels of these antibodies after receiving the Moderna vaccine predicted the amount of protection.

Protection after exposure in primates provides an estimate for the strength of neutralising antibodies needed to prevent Covid-19 in people too. Reassuringly, even small amounts of neutralising antibodies were effective at protecting against Sars-CoV-2.

A third approach is to compare biomarkers in people who received the vaccine and were protected against those who still had breakthrough infection or symptomatic disease. Some vaccinated people are infected since none of the vaccines are 100% effective in preventing infection or symptomatic Covid-19. The goal here is to compare the two sets of people and see if the levels of neutralising antibodies in a person is a good predictor of protection from breakthrough cases.

Data from the Oxford vaccine group examined neutralising antibody levels 28 days after the second dose of the AstraZeneca vaccine. Preliminary results, which were posted on medRxiv on June 24, show that high levels of spike-protein and receptor-binding domain specific neutralising antibodies correlate with a lower chance of symptomatic Covid-19. However, correlation with asymptomatic infection was not established.

How should we interpret these three studies on neutralising antibodies? Antibodies are only one arm of the immune system and there are redundancies in immunity: T cells have substantial contribution in protection against Covid-19. They can step in to offer protection when antibody levels decline or variants emerge that evade antibody recognition.

It helps to think of immune protection as a sliding scale from ideal scenario of preventing infection altogether, to asymptomatic infection, to symptomatic Covid-19 progressing in the order of mild, moderate, and severe disease requiring hospitalisation. Complete protection would result in no infection or symptoms. Incomplete protection would reduce the severity of disease.

Strong levels of neutralising antibodies that bind well to virus help prevent infection and replication in the body. However, a combination of antibody and T cells can prevent severe Covid-19 and hospitalisation. Loss of antibodies or the inability to make them might not reduce protection against serious disease. Even after infection, antibody levels wane after an acute immune response phase. However, memory B cells and long-lived plasma cells can help the immune system kickstart a rapid response on re-exposure to the virus.

High levels of spike-protein-specific antibodies seem to be a good predictor of strong immune protection. But it isn’t clear that low levels correspond with loss of protection in all cases. For example, neutralising antibodies after the first dose of either Moderna or Pfizer vaccine are low, in contrast with real-world protection in either scenario.

Still, the preliminary data are encouraging. Earlier this month, Nature ran a story that the United Kingdom might approve an inactivated Sars-CoV-2 vaccine by Valneva if it elicits more antibodies in a 4,000 participant trial than that obtained after vaccination with two doses of AstraZeneca.

Anirban Mahapatra, a microbiologist by training, is the author of COVID-19: Separating Fact From Fiction

These are his personal views