Immune responses to mRNA vaccines : characteristics & the impact of host immune status

<p dir="ltr">mRNA vaccines played a critical role in combating the SARS-CoV-2 pandemic and are progressing toward wider clinical use. However, much of how mRNA vaccines act upon the immune system to induce protection remains incompletely understood. This thesis explores how mRNA vaccines interact with the cells of the immune system, focusing on B cell immunity, early inflammation, and host-specific factors.</p><p dir="ltr">In study I, we compared a preclinical nucleoside-unmodified mRNA vaccine candidate against an antigen-matched inactivated virus vaccine. We found that two doses of unmodified mRNA vaccine induced higher peak neutralizing antibody titers and bone marrow plasma cell counts, while showing similar memory B cell somatic hypermutation and diversity. Antibody titers were cross- neutralizing and stabilized at a higher plateau at 1 year after mRNA compared to inactivated virus vaccination.</p><p dir="ltr">In study II, we investigated how prior SARS-CoV-2 influence the early innate immune responses to nucleoside-modified mRNA vaccination in humans. We showed that mRNA vaccination induces a transient inflammatory response including moderate systemic release of proinflammatory cytokines, upregulation of type I interferon associated genes, and proportional expansion of circulating monocyte populations. In individuals with known prior SARS-CoV-2 infection, the magnitude of the innate response to the prime vaccination was increased compared to SARS-CoV-2 naïve controls. Correlation analysis associated innate immune activation to levels of pre-existing adaptive immunity.</p><p dir="ltr">In study III, we investigated the B cell response to SARS-CoV-2 mRNA vaccination in hematopoietic stem cell transplant recipients. While those vaccinated within 12 months post-transplant had reduced antibody and memory B cell levels, the responses that did occur were functional in terms of neutralization and accumulation of somatic hypermutation in the B cell receptor. Lower responses were associated with elevated fractions of immature transitional B cells.</p><p dir="ltr">In summary, this thesis provides insights into both the early and long-term immune responses elicited by mRNA vaccines and underscores the influence of individual host factors, such as prior antigen experience and immune repertoire composition, on vaccine responsiveness.</p><h3>List of scientific papers</h3><p dir="ltr">I. <b>Hellgren F*</b>, Cagigi A*, Arcoverde Cerveira R*, Ols S, Kern T, Lin A, Eriksson B, Dodds MG, Jasny E, Schwendt K, Freuling C, Müller T, Corcoran M, Karlsson Hedestam GB, Petsch B, Loré K. Unmodified rabies mRNA vaccine elicits high cross-neutralizing antibody titers and diverse B cell memory responses. Nature Communications. 2023 Jun 22;14(1):3713. <a href="https://doi.org/10.1038/s41467-023-39421-5">https://doi.org/10.1038/s41467-023-39421-5</a></p><p dir="ltr">II. <b>Hellgren F*</b>, Rosdahl A*, Arcoverde Cerveira R, Lenart K, Ols S, Gwon YD, Kurt S, Delis AM, Joas G, Evander M, Normark J, Ahlm C, Forsell MN, Cajander S, Loré K. Modulation of innate immune response to mRNA vaccination after SARS-CoV-2 infection or sequential vaccination in humans. JCI Insight. 2024 May 8;9(9):e175401. <a href="https://doi.org/10.1172/jci.insight.175401">https://doi.org/10.1172/jci.insight.175401</a></p><p dir="ltr">III. <b>Hellgren F,</b> Arcoverde Cerveira R, Lindgren G, Chen P, Lenart K, Ols S, Cagigi A, Rocavert Barranco M, Shaloom Vitus E, Corcoran M, Gwon Y-D, Forsell MNE, Evander M, COVAXID Study group, Bergam P, Buggert M, Ljunggren H-G, Aleman S, Karlsson Hedestam GB, Björklund A, Nordlander A, Ljungman P, Mielke S*, Loré K *. The impact of B cell reconstitution on mRNA vaccine responses in allogeneic stem cell transplant recipients. [Manuscript]</p><p dir="ltr">*= Equal contribution.</p>