mRNA Vaccine Beats Infection for Key Defense against COVID-19: Stanford Scientists

If, for any reason, killer T cells arenʼt abundant enough or donʼt get sufficiently activated, a virus that has ducked the bodyʼs antibody defense and established a beachhead inside a cell gets extra time to commandeer that cellʼs productive machinery, forcing it to produce copious copies of the virus and send its progeny off to invade other cells.

Investigating the Vaccine
Soon after the Pfizer-BioNTech-designed COVID-19 vaccine became available, Davis, who directs Stanfordʼs Institute for Immunity, Transplantation and Infection, and his colleagues set out to determine how it worked. (No equivalent analysis was performed on the Moderna vaccine.)

Most investigations of vaccine efficacy have focused on these productsʼability to generate antibodies, whose infection-blocking effectiveness can be measured in laboratory glassware with relative ease. T cells have proved tougher to study. But Davis, who over several decades has pioneered the exploration of killer T cells and their cousins, helper T cells, has advanced their analysis by designing and championing ever-better methods for monitoring their more complex and more subtle interactions with their targets.

Helper T cells, more managerial in nature than killer T cells, are instrumental in inducing antibody production by another immune-cell type called B cells.

Davis noted that the way T cells recognize antigens differs from the way antibodies recognize antigens, rendering T cells less likely to be fooled and defeated by tiny mutations in viral sequence (strain variants) than antibodies.

For the new study, Davis and his colleagues were armed with state-of-the-art technology, pioneered by Mallajosyula in Davisʼslab, that permitted them to precisely measure changes in levels of killer T cells directed specifically at cells infected by SARS-CoV-2. The researchers analyzed blood samples from three categories of study participants: people with no history of prior SARS-CoV-2 infection who were getting their first and second doses of the new mRNA vaccine, unvaccinated COVID-19 patients, and those getting the vaccine whoʼd previously been infected by the virus but who had now recovered —at least, apparently.

The researchers monitored the proliferation and activation of killer T cells specifically directed against SARS-CoV-2 in these individuals, drawing blood at several time points starting on the day of their first vaccine dose — or, in unvaccinated COVID-19 patients, on the first day they manifested symptoms.

Uninfected vaccine recipients experienced a greater than 60-fold rise in their levels of SARS-CoV-2-targeting killer T cells. By six weeks later their first dose, one in every five of their killer T cells was SARS-CoV-2- specific.

COVID-19 patients showed more lackluster results: Average levels of their total SARS-CoV-2-specific killer T cells were less than one-tenth those of infection-free vaccinees — despite the fact that the vaccine contains only one part of the virus (the so-called spike protein SARS-CoV-2 uses to latch onto cells) while infection by the actual virus can generate killer T cell responses to multiple components.

Recovered COVID-19 patientsʼSARS-CoV-2-specific response to vaccination also lagged behind that of never-infected participantsʼresponse. Three weeks later the second dose of the two-dose mRNA-vaccine regimen, killer T cells narrowly targeting SARS-CoV-2 were less than one-seventh as prevalent in previously infected vaccineesʼblood as they were in the blood of never-infected vaccinees at the same time point.

These cells, moreover, seemed less warlike, by virtue of the signaling substances they secreted, in previously infected than in never-infected vaccine recipients.

Helper T cells were not strongly affected by prior SARS-CoV-2 infection. In contrast to killer T cellsʼin-your- face behavior, these cells play a more managerial role. This includes encouraging antibody production by other immune cells called B cells.

Antibody production upon reinfection of former SARS-CoV-2 patients remains robust, Davis said.

“But antibodies mostly only block infection — theyʼre much less able to root out established infections,”he said. “Only killer T cells can do that. We think the infection-induced shortage of functional killer T cells may be one factor thatʼs helping give rise to long COVID, because these impaired killer T cell populations arenʼt adequately eliminating all infected cells —and theyʼre becoming exhausted in trying to do so.”

Bruce Goldman is a senior science writer in the Office of Communications. The article was originally posted to the website of Stanford Medicine.