Question: I was reading that the longer spacing between first and second doses of the AstraZeneca vaccine (12 weeks vs. 6 weeks), the better the immune response.  Why would the timing of the second dose matter?

Answer: Here’s a wee bit of background, hypotheses, and a finally, a more direct answer to your question.

Background. Vaccines work by imitating an infection that causes the immune system to respond by developing B-cells and T-cells that remember how to fight the disease in the future. This immunological memory is the basis of long-term protection.  To use an analogy, when we’re learning something new, one lesson often doesn’t cut it; we need refresher training to make sure that the lesson sticks.  So it goes with our immune system’s memory– sometimes it takes more than one lesson for your immune system to fully learn and remember how to respond, hence the need for a booster shot. For quick refresh on how the immune system works, see Q&A of 5/9. 

Hypotheses. Because our immune systems are complicated and there’s still a lot that we are learning, we still don’t know what the optimal time for boosting is and whether it varies based on vaccination-type.  Some evidence suggests that an interval of at least 2-3 months between the prime and the boost is necessary for optimal immune response.  Meanwhile, evidence from computational simulations indicates that an interval of “several weeks between the prime and the boost is necessary to obtain optimal responses… efficiency increases when the second dose is given 45 to 90 days after the prime whereas further delaying the boost does not improve the secondary antibody peak.”  The hypothesized reason for the importance of a boosting interval is that the memory T cells take several weeks to form after the first shot, and memory B cells have to go through a germinal center (lymph nodes and spleen) maturation process that can take several months. Scientists also hypothesize that the innate immune system may contribute to the boosting effect of the second dose if enough time is given for special innate system cells to develop.  

Answer. To ensure that your immune system has fully learned the lesson and is ready, willing, and able to respond when it encounters the real virus, it would benefit to wait to give the second dose until the memory T cells and B cells have developed, and the innate immune system is primed.  This requires an interval of at least 3-4 weeks, but evidence from various studies indicates that an interval of 2-3 months may be superior.