Rabies mRNA vaccine induces long-lasting immune response in macaques

In a recent study published in Nature Communicationresearchers are studying the impact of messenger ribonucleic acid (mRNA) rabies vaccine on B-cell memory response and cross-neutralizing antibody titers.

Study: Unmodified rabies mRNA vaccine elicits high titers of cross-neutralizing antibodies and diverse B-cell memory responses. Image Credit: Kateryna Kon/Shutterstock.com

A new rabies vaccine

The main mode of transmission of the rabies virus (RABV) to humans is through the bite of infected animals. Recently, a vaccine consisting of a specific sequence of unmodified nucleoside mRNA encoding RABV-G complexed with protamine was shown to produce neutralizing antibodies that effectively protect vaccinated individuals against lethal RABV infection in various animal models.

In the present study, the quality and characteristics of immune responses induced by this RABV-G mRNA vaccine were investigated in comparison to Rabipur, an inactivated whole virus vaccine. Non-human primates (NHPs) were immunized with a high dose of mRNA vaccine and their responses ranging from early innate immune activation to the quality and titers of antibodies collected up to one 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 received 100 μg mRNA vaccine, while group three received Rabipur. Groups two and three received 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.

The vaccines were administered by intramuscular injection. Peripheral blood samples and bone marrow aspirates were collected at various intervals throughout the 50-week study.

Study results

mRNA vaccination increased blood levels of interferon-alpha (IFNα) and IFN-inducible I-TAC/CXCL11, which were not detected in Rabipur recipients. Additionally, the mRNA vaccine produced higher levels of interleukin receptor 1 (IL-1RA) antagonist, chemokine eotaxin, and monocyte chemotactic protein 1 (MCP-1) compared to values basic.

Immunization with either vaccine did not cause significant changes in complete blood count (CBC) and clinical chemistry, nor did the vaccines elevate body temperature or have any d negative impact on body weight.

Almost all animals developed rabies virus neutralizing antibody (RNAV) titers above the threshold recommended by the World Health Organization (WHO) two weeks after primary vaccination. Unlike the mRNA-vaccinated cohorts, the Rabipur group showed reduced titers four weeks after the first 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 showed consistently high antibody titers. The kinetics of RABV-G binding immunoglobulin G (IgG) titers were similar to neutralizing titers. After vaccination, all cohorts had detectable levels of RABV-G specific IgM.

Plasmablasts secreting antibodies specific for RABV-G were detected by ELISpot four days after the booster dose immunization. To this end, the mRNA prime-boost cohort had higher frequencies of these plasmablasts compared to the Rabipur cohort.

After initial immunization, all groups had detectable RABV-G specific plasma cells in their bone marrow. Notably, RABV-G-specific circulating memory B cells (MBCs) increased after booster immunization in the mRNA group and remained detectable 18 weeks later. Moreover, cells secreting MBC-derived antibodies were still detectable in the mRNA group, especially in the prime-boost cohort, at week 50.

mRNA vaccine recipients had reduced CD4+ T cell responses after initial vaccination; however, these T cell levels increased after the booster vaccination, with no CD4+ T cell response detected in Rabipur recipients. All groups showed undetectable or weak CD8+ T cell responses.

There was a progressive increase in mean per animal somatic hypermutation (SHM) of RABV-G-specific MBCs observed in both groups from two weeks post-boost to 12 weeks post-boost. No significant variation in SHM was detected between the groups.

conclusion

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. Similarly, mRNA vaccination led to stronger immune responses than the Rabipur vaccine when given in the same schedule at two doses spaced four weeks apart. The mRNA vaccine also induced stronger neutralization as well as higher frequencies of B cells and plasma cells.

These results indicate that this type of mRNA vaccine could be an advantageous alternative to currently approved rabies vaccines for pre- and post-exposure prophylaxis.