Vaccine-induced SARS-CoV-2-specific T cell responses in patients with X-linked Agammaglobulinemia

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ABSTRACT The SARS-CoV-2 pandemic has resulted in enormous loss of life and in long-lasting health sequalae in a subset of convalescent patients. Little is known about the impact of SARS-CoV-2 infection on people with primary immune deficiency diseases (PIDD). There is also a lack of guidelines regarding the inclusion of people with PIDD in SARS-CoV-2 vaccination efforts. Among PIDD, primary antibody deficiencies are most prevalent. X-linked agammaglobulinemia (XLA) is a genetic disorder that is estimated to occur in 1 of 200,000 births and is caused by a mutation in Bruton tyrosine kinase (BTK) that leads to an arrest in B cell development. Thus, XLA patients cannot mount antibody responses and require lifelong therapy with gammaglobulin infusions to prevent infections. These infusions, however, do not contain antibodies to the recently emerged SARS-CoV-2 virus leaving these patients vulnerable to COVID-19. The currently approved SARS-CoV-2 vaccines are thought to mediate protection against infection through the induction of neutralizing antibodies. However, all current SARS-CoV-2 vaccine candidates have the potential to elicit humoral and T cell responses. Although T cell responses cannot protect against viral infection, anti-viral T cell responses are critical in the control of virus replication and dissemination. In XLA patients, T cell responses are considered to be normal. Thus, we hypothesize that the currently approved SARS-CoV-2 mRNA vaccines will elicit persistent Spike protein-specific T cell responses with the potential to protect against disease against the vaccine strain and variants of concerns. Support for our hypothesis is provided by data documenting that XLA patients receiving the inactivated influenza vaccine can mount protective influenza-specific T cell responses at a similar magnitude and quality as immunocompetent individuals. Aim 1 of the proposed studies will assess magnitude, function, durability, and breadth of SARS-CoV-2 specific T cell responses in XLA patients prior to and at week 1, week 3, 4 months and 1 year after vaccination and/or boost with one of the two approved SARS- CoV-2 Spike protein mRNA vaccines. XLA patients, however, can encompass a broad spectrum of BTK mutations. Some BTK mutations can inhibit Toll-like receptor signaling and other innate functions in monocytes and dendritic cells. Both monocytes and dendritic cells are important in the priming and activation of antigen- specific T cells. Therefore, Aim 2 of the proposed studies, will assess the function of monocytes and dendritic cells in XLA participants and correlate these functional parameters to vaccine-induced T cell responses in the same patient. To perform the studies, we will leverage well-established cohorts of XLA patients at Duke, UNC, and USF. The results of our study are expected to inform health policies regarding the inclusion of XLA patients in SARS-CoV-2 vaccination efforts and provide the foundation for larger studies with other PIDD populations.