In the two previous installments (one, two) of what has now become my praise of T cells, I explained that the SARS-CoV-2 protein sequences recognized by T cells do not change, likely explaining why vaccines prevent serious disease and death caused by any variant. Today I will explain that virus-specific T cells appear a week after mRNA vaccination when neutralizing antibodies are weakly detectable. Their presence is likely responsible for vaccine-mediated protection against severe disease.
Since the first COVID-19 vaccines were tested in clinical trials, much has been made of their ability to block infection. At ten days after the first vaccine dose, clear protection against severe disease is observed. But at this early time, neutralizing antibodies can barely be detected. That job is likely being done by T cells, the other arm of the adaptive immune response.
T lymphocytes come in two broad types: CD8+ and CD4+. The former, also known as cytotoxic T lymphocytes (CTLs) can recognize a virus infected cell and kill it (pictured). The latter T cells produce cytokines that are important for maturation of both CTLs and B cells, the antibody-producing cells. The importance of antibody versus T cells in controlling infection depends on the virus. For many viruses, antibody can block infection, but T cells are important for recovery. In COVID-19, antibodies rise late in the course of infection, when virus titers are already declining. This observation is in line with the resolution of infection by T cells.
People with agammaglobulinemia, who cannot make antibodies, or who have been depleted of B cells do not have a serious course of COVID-19, further supporting a role for T cells in preventing severe disease.
During the trials of mRNA vaccines it was observed that protection against severe COVID-19 arose at 10 days after the first inoculation, a time when neutralizing antibodies are barely detectable in serum. The logical candidate for this effect is the T cells.
To address this question, a group of mRNA vaccine recipients were sampled at different times after the first and second doses. CD8+ T cells in blood were examined for the ability to recognize a few spike-specific epitopes. A rapid and substantial induction of CD8+ T cells in these individuals was observed beginning at 6-8 days after the first vaccine dose. At this time, neutralizing antibodies in sera of these subjects were barely detectable. CD8+ T cell numbers are substantially increased by the second vaccine dose, which also leads to much higher levels of neutralizing antibodies. CD4+ T cells are also detected after the first vaccine dose and likely coordinate the expansion of CD8+ T cells and B cells.
mRNA vaccination also induces spike-specific memory B and T cells which circulate for at least several months. Their exact longevity remains to be determined by longer term studies.
The gradual escape of multiple variants of concern from neutralization by sera from vaccinated individuals has been met with alarm by public health officials. At least one prominent leader has suggested that the virus might even mutate so as to escape vaccine protection. An even cursory examination of the facts reveals otherwise. Despite reduced neutralization by vaccine-induced antibodies, vaccine recipients are still protected from severe disease and death by all variants. In contrast to changing B cell epitopes, T cell epitopes do not change in any variant. Furthermore, virus-specific T cells are induced early after the first mRNA vaccine dose, and confer protection against severe COVID-19 at a time when neutralizing antibodies are barely detectable. These observations indicate that T cells will save us from COVID-19.
In vaccinology, the correlate of protection refers to what is needed – antibodies or T cells – to protect from infection or disease. High levels of antibodies appear to correlate with protection against infection by SARS-CoV-2. However, when antibody levels decline, as they always do after infection or vaccination, infection can no longer be prevented. In this case, protection against severe disease and death is accomplished by T cells.