In a recent study published in Nature Communications, researchers explore the impact of the rabies messenger ribonucleic acid (mRNA) vaccine on B-cell memory response and cross-neutralizing antibody titers.
Study: Unmodified rabies mRNA vaccine elicits high cross-neutralizing antibody titers and diverse B cell memory responses. Image Credit: Kateryna Kon / Shutterstock.com
A novel rabies vaccine
The primary mode of transmission of the rabies virus (RABV) to humans is through bites from infected animals. Recently, a vaccine consisting of a specific sequence of nucleoside-unmodified mRNA encoding RABV-G complexed within protamine was found to produce neutralizing antibodies that effectively protect vaccinated individuals against fatal RABV infection in various animal models.
In the present study, the quality and features of immune responses elicited by this RABV-G mRNA vaccine were investigated in comparison to Rabipur, a whole inactivated virus vaccine. Non-human primates (NHPs) were immunized with a high mRNA vaccine dose and their responses ranging from early innate immune activation to the quality and titers of antibodies sampled up to a year later were analyzed.
About the study
A total of 18 Chinese rhesus macaques were included in the study and separated into three groups based on their weight and sex. Groups one and two were administered 100 μg mRNA vaccine, whereas group three received Rabipur. Groups two and three were administered a second dose of their respective vaccines four weeks after the initial dose to compare the responses of two groups undergoing a similar immunization process.
Vaccines were administered through intramuscular injection. Peripheral blood samples and bone marrow aspirates were collected at various intervals throughout the 50-week study.
The mRNA vaccination increased levels of interferon-alpha (IFNα) and IFN-inducible I-TAC/CXCL11 in the blood, both of which were not detected in Rabipur recipients. Additionally, the mRNA vaccine produced higher levels of interleukin 1 receptor antagonist (IL-1RA), the chemokine Eotaxin, and monocyte chemoattractant protein 1 (MCP-1) as compared to baseline values.
Immunization with either vaccine did not cause significant changes in complete blood counts (CBC) and clinical chemistry, nor did the vaccines did increase body temperature or have a negative impact on body weight.
Almost all animals developed rabies virus-neutralizing antibody (RVNA) titers over the World Health Organization (WHO)-recommended threshold two weeks following prime immunization. Unlike the mRNA-vaccinated cohorts, the Rabipur group exhibited reduced titers four weeks after the prime vaccine dose.
At week 18, all three cohorts had RVNA titers above the WHO threshold. Throughout the 50-week study period, only boosted mRNA vaccine recipients exhibited consistently high antibody titers. The kinetics of RABV-G binding immunoglobulin G (IgG) titers were similar to the neutralizing titers. Following vaccination, all cohorts exhibited detectable levels of RABV-G-specific IgM.
Antibody-secreting plasmablasts that were specific to RABV-G were detected by ELISpot four days following booster dose immunization. To this end, the mRNA prime-boost cohort had higher frequencies of these plasmablasts as compared to the Rabipur cohort.
After the initial immunization, all groups exhibited detectable RABV-G-specific plasma cells in their bone marrow. Notably, RABV-G specific circulating memory B-cells (MBC) increased after boost immunization in the mRNA group and remained detectable 18 weeks thereafter. Furthermore, MBC-derived antibody-secreting cells were still detectable in the mRNA group, particularly in the prime-boost cohort, at week 50.
The mRNA vaccine recipients exhibited reduced CD4+ T-cell responses after the initial immunization; however, these T-cell levels increased following booster vaccination, with no CD4+ T-cell responses detected in Rabipur recipients. All groups exhibited undetectable or low CD8+ T-cell responses.
There was a gradual rise in the per-animal average somatic hypermutation (SHM) of RABV-G-specific MBCs observed in both groups from two weeks after the boost to 12 weeks after the boost. No significant variation in SHM was detected among the groups.
The two-dose strategy using the mRNA vaccine resulted in higher antibody titers as well as higher RABV-G-specific cell populations compared to the inactivated virus vaccine. Likewise, mRNA vaccination led to stronger immune responses than the Rabipur vaccine when given in the same two-dose, four-week spaced schedule. The mRNA vaccine also induced stronger neutralization along with higher frequencies of B-cells and plasma cells.
These findings indicate that this type of mRNA vaccine could be a beneficial alternative to the currently approved rabies vaccines for pre- and post-exposure prophylaxis.
- Hellgren, F., Cagigi, A., Arcoverde Cerveira, R., et al. (2023). Unmodified rabies mRNA vaccine elicits high cross-neutralizing antibody titers and diverse B cell memory responses. Nature Communications 14(1); 1-15. doi:10.1038/s41467-023-39421-5