Exploring immunity, biodistribution, and toxicity of novel vaccines

This PhD thesis aimed to enhance the understanding of innate immunity, biodistribution, and safety through the study of modern immunostimulatory formulations, including an mRNA vaccine and an anti-CD40 monoclonal antibody (mAb), in non-human primate (NHP) models. The research was divided into three key studies:

Paper I focused on the unmodified mRNA vaccine CVnCoV, which encodes the SARS-CoV-2 spike protein. The study examined early innate immune responses, biodistribution, and adaptive immune responses in NHPs following a low-dose regimen. This study highlighted the importance of optimizing vaccine doses to balance safety and efficacy, as lower doses resulted in limited antigen dissemination to lymph nodes, affecting the priming of adaptive immunity. However, additional doses were able to partly rescue suboptimal responses.

Paper Il explored the development and evaluation of MAB273, a novel Fcy- receptor-independent agonistic anti-CD40 mAb, as an immunostimulatory adjuvant. The study assessed its binding and activation properties in vitro, as well as its safety, immune activation, pharmacokinetics, and tissue targeting in vivo. MAB273 effectively activated immune cells without relying on FcyR crosslinking. It also showed promise as an adjuvant, enhancing CD4 and CD8 T cell responses in both therapeutic and prophylactic vaccination models. MAB273 could thus represent a potential immunostimulatory adjuvant, deserving additional investigation in both therapeutic and preventive vaccination strategies.

Paper III established age- and species-specific reference intervals for biochemical and hematological parameters in rhesus and cynomolgus macaques, which are critical for evaluating vaccine and drug safety. The study revealed that vaccination triggered transient inflammatory responses, with most parameters returning to baseline within 1-2 weeks. Key biomarkers, such as ALT and BUN, were important for assessing vaccination-induced effects on the liver and kidneys. This study also suggested a potential link between innate immune activation and adverse vaccine responses, warranting further investigation.

Collectively, these studies contribute valuable insights into immunological mechanisms and safety, with implications for future vaccine development.

List of scientific papers

I. Lenart K, Hellgren F, Ols S, Yan X, Cagigi A, Cerveira RA, Winge I, Hanczak J, Mueller SO, Jasny E, Schwendt K, Rauch S, Petsch B, Loré K. A Third Dose of the Unmodified COVID-19 mRNA Vaccine CVnCoV Enhances Quality and Quantity of Immune Responses. Molecular Therapy - Methods & Clinical Development. 2022 Dec 8;27:309-323. https://doi.org/10.1016/j.omtm.2022.10.001

II. Yan X, Ols S, Arcoverde Cerveira R, Lenart K, Hellgren F, Ye K, Cagigi A, Buggert M, Nimmerjahn F, Falkesgaard Højen J, Parera D, Pessara U, Fischer S, Loré K. Cell Targeting and Immunostimulatory Properties of a Novel Fcy- Receptor-Independent Agonistic Anti-CD40 Antibody in Rhesus Macaques. Cellular and Molecular Life Sciences. 2023 Jun 23;80(7):189. https://doi.org/10.1007/s00018-023-04828-2

III. Yan X, Arcoverde Cerveira R, Ols S, Lenart K, Hellgren F, Engstrand O, Reinhardt A, Eriksson B, Loré K. Biochemical and Hematological Reference Intervals in Macaca mulatta and Macaca fascicularis: Implications for Vaccine and Drug Development. [Manuscript]