Although clinical studies of vaccine efficacy will ultimately be needed

we must also begin now to investigate correlates of human immunity after both natural SARS-CoV-2 infection and vaccination, including by evaluating the durability of responses and their localization (mucosal and systemic).

Human challenge [!] studies with the human "cold virus" coronaviruses (e.g., OC43) will probably be important.

Fourth doses of the COVID-19 vaccine don't appear to offer significant protection against catching omicron according to a preliminary study conducted in Israel, the first country to authorize a [first and] second booster for its general population.
[...]
These findings appear to confirm doubts expressed by the European Union's top drug regulator last week. Marco Cavaleri, the European Medicines Agency's head of vaccines strategy, said at a news briefing there's no data supporting the broad effectiveness of fourth boosters.
[...]
Researchers say that although it's true that there's no clinical data proving the effectiveness of multiple boosters, there's also no science to back up the idea that frequent boosters could cause "fatigue" in the population. That's because the research has never been attempted.
[...]
While T cell [B-cell?]exhaustion can be observed in cancer or HIV patients in response to some immune-based treatments, it's never been observed in humans in response to frequent COVID-19 vaccination. Obst said that although there's little clinical data behind it, Cavaleri's concern makes sense.
[...]
The COVID-19 vaccines have been held to an impossible standard, he said. When the phase three studies on the quality of the Moderna and Pfizer vaccines were presented in the US in December 2020, they showed claimed a 95% efficacy against mild [COVID-19] illness.

The study did not explain why protection against reinfection and hospitalization grew among those individuals with a prior infection during Delta.

The study, published Wednesday, looked at four categories of people in New York and California -- individuals who were unvaccinated with and without a prior infection and vaccinated people with and without a prior infection.
[...]
Eli Rosenberg, deputy director for science at the New York State Department of Health who helped with the study, said "the totality of the evidence suggests ... that both vaccination and having survived Covid each provide protection against subsequent infection and hospitalization." "Either of those provides protection, and only one of those is the safe choice that we would recommend. And that's vaccination," he said.

Protection against Delta was highest, however, among people who were both vaccinated and had survived a previous COVID infection, and lowest among those who had never been infected or vaccinated, the study found.

well, alrighty then
archivedSCOTUS oral argument, NFIB v. Dept. of Labor

JUSTICE SOTOMAYOR: Others, unvaccinated people at risk and people who are vaccinated. They may be at a lesser risk, but the grave risk remains to people of all ages and conditions that are unvaccinated.
MR. FLOWERS: Right, but -- but the problem is they've defined numerical probabilities that are equal to be grave in one case and not grave in the other, and that is the definition of irrational.