The efficacy of COVID-19 vaccines depends in a complex way on the strength of the prime doses and the time interval between the prime doses and the booster shots. A computer simulation study carried out by researchers at Indian Institute of Science, Bengaluru (IISc) attempts to understand how this works. The research is published in the journal Frontiers in Immunology.
Earlier observations from the trials of the Oxford–Astra Zeneca vaccine have shown that immune response of people given prime doses and booster doses depended on the strength of the primer and the interval between the prime and boosters in a counter-intuitive way. The efficacy in preventing symptomatic infection was 63.1% when a standard dose containing 5 X 10 10 virus particles was administered for both prime and booster. On the other hand, if a low dose prime, consisting of 2.2 X 10 10 virus particles, was administered, there was a higher efficacy observed of 80.7%.
Similarly, when the interval between the prime and booster was less than six weeks, an efficacy of 55.1% was seen, which rose to 81.3% at 12 weeks or greater, when standard doses were used for both prime and booster.
Studies are being conducted to study the effect of dose strength and intervals between prime and booster for Pfizer-BioNTech and Moderna vaccines too.
Understanding how this operates will be useful in determining the delivery of vaccines in circumstances where there is shortage of vaccines. It will also help in optimising the effect of vaccines.
"Why low dose prime or delayed boost improves COVID-19 vaccine efficacies is not well understood, and this hinders optimal vaccine usage which is critical given limited supplies. Our study presents a plausible explanation,” says Narendra Dixit from IISc’s Department of Chemical Engineering who led the work that has been published in Frontiers in Immunology.
With the above observations in mind, researchers from Indian Institute of Science, Bengaluru, and University of Queensland, Brisbane, Australia, made a computer simulation to study how the creation and proliferation of B cells happens in the germinal centres of the body’s immune system.
The role of cellular immunity is not fully understood, but studies suggest that the efficacy of the COVID-19 vaccines is proportional to the number of neutralising antibodies they elicit. Germinal centres are the places where the cells that produce antibodies are selected for. These are temporary structures that form in lymphoid organs, for periods ranging from a few weeks to several months.
In the germinal centres, B cells are selected based on the ability of their receptors to bind to the antigen presented as immune complexes. In the case of the COVID-19 vaccines, the antigen in question would be the part of the spike protein.
The researchers simulated a model of the germinal centre reaction in the computer and studied the effect of low prime dose and long interval between prime and booster shots given equal prime doses.
The hypotheses they tested were the following: In the case of a smaller prime dose, in the germinal centre, there are fewer available antigens (spike protein attached to immune complexes) for the B cell receptors to bind to, therefore only those B cells that show a higher efficiency in reaching and binding to the antigen would survive and grow. Those B cells that fail to bind would die out. Therefore, this results in the selection of the B cells with higher propensity for antigen-binding. Once a booster is given, these B cells which have a higher affinity for the antigen are multiplied, and therefore the efficacy of the vaccine in preventing symptomatic illness would also be higher.
In the case of equal prime shots and delayed booster what would happen, the researchers hypothesised, was that during the longer interval, because antigen levels go down with time, only those B Cells that had a higher affinity for antigen would survive and the others would have died out and therefore, when the booster was given, it would multiply such B cells having higher affinity.
In their simulations, the researchers saw that this did indeed take place.
Further studies needed
“Our prediction is based on comprehensive computer simulations of the process underlying antibody production in our body in response to vaccination. Future studies may validate the explanation using experiments, paving the way for rational optimisation of vaccine deployment strategies," says Prof. Dixit.
If the predictions are verified by experiments, they can guide the protocols of giving out vaccine shots and booster doses in a more efficient manner, which is crucial now.