Does mRNA-based heterologous prime-boost vaccination work?

Due to the severe acute respiratory illness coronavirus 2’s rapid spread, there has been an increase in the development of coronavirus disease 2019 (COVID-19) vaccines in numerous nations (SARS-CoV-2).

The messenger RNA (mRNA) component of the next-generation RNA vaccination platform serves to encode the target antigen. The original idea for an mRNA vaccine was developed in 1990, but its use was constrained by mRNA’s poor in vivo transport, instability, and high level of innate immunogenicity.
Such restrictions can be addressed with the aid of technological developments in lipid nanoparticles (LNPs) and the introduction of nucleoside modification by pseudouridine. No integration of the mRNA into the host genome occurs. This enables cell-free mRNA manufacturing, resulting in affordable, scalable, and quick production.

The US Food and Drug Administration (FDA) approved two COVID-19 mRNA vaccines (Pfizer/BioNTech BNT162b2 and Moderna mRNA-1273) for use in emergency situations within a year of their development. Worldwide administration of additional COVID-19 vaccines, including viral vector and inactivated vaccines, has also received approval.
Recently, the FDA approved Novavax, a conventional protein subunit vaccine, for use in emergency situations. Due to the accessibility of these vaccines, patients are now being immunized against a single virus using a heterologous prime-boost vaccination strategy.

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Heterologous prime-boost techniques to increase T-cell responses and neutralize antibody titers have been described in studies. However, it is unknown if heterologous priming-boosting with mRNA and protein vaccines will be effective and immunogenic. Additionally, there is no information on how the order of vaccinations affects vaccine effectiveness.

The influenza virus is a significant zoonotic pathogen that annually causes 290,000 to 650,000 fatalities worldwide and 3 to 5 million cases of severe illness. The introduction of novel pandemic strains or an inability to forecast the vaccine strain can reduce the efficacy of current influenza vaccinations, which are nonetheless effective against the virus. Therefore, it’s crucial to create an influenza vaccine that can be manufactured quickly.

Many influenza vaccines that encode the seasonal influenza strain’s hemagglutinin (HA) are now in the preclinical stage, while a few quadrivalent and monovalent vaccines are currently undergoing clinical trials.

A recent study examined whether the order in which different vaccine types were administered affected the efficiency of a heterologous prime-boost vaccination strategy. The results are available as a preprint on Research Square* and are now being reviewed at NJ Vaccines.

Concerning the study
Female BALB/c mice that were six weeks old participated in the study, and they were given a week to acclimate before the trial. A DNA fragment that encoded the influenza A virus’s HA protein was used to create the DNA template for the mRNA vaccine, and then mRNA-HA was synthesized. Then, 10 g of mRNA was used to transfect Vero cells, and a western blot was performed afterward.

LNPs were developed along with their characterization. Mice were immunized every two weeks with either 1 or 5 g of HA protein or mRNA. Antibody levels were assessed by Elisa, then an ELISpot assay.

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Following the virus challenge, clinical disease, survival, and body weight of infected mice were evaluated. Total RNA was used for real-time polymerase chain reaction (PCR) using bronchoalveolar lavage fluid (BALF) and lung samples. The collection of BALF and histological analyses were completed.

Study results
According to the findings, protein-HA priming resulted in an IgG1-biased response while priming produced significant levels of IgG2a. Balanced IgG1/IgG2a responses were seen after homologous mRNA-HA immunization (R-R) and heterologous mRNA-HA/protein-HA immunization (R-P).

In comparison to the P-R group, the R-P group was found to have higher levels of microneutralization (MN) and hemagglutination inhibition (HI). The interferon (IFN) cytokine-producing cells in splenocytes did not differ significantly between the R-P and P-R groups.

The R-P group was shown to have a larger frequency of antigen-specific IFN-producing CD4 + T cells than the P-P and P-R groups. While interleukin-2 (IL-2)-producing cells in CD4 + T cells were more prevalent in the P-R and R-P groups, the R-R group also showed a greater frequency of IFN- or TNF-producing cells in CD8 + T cells. Additionally, the R-P and P-R groups were shown to have greater CD4 + and CD8 + T cell counts than the P-P group.

The P-P and R-R groups showed different gene expression patterns, but not the R-P and P-R groups. Increased mast cell pathways and neutrophil degranulation were seen in the P-P and P-R groups. Additionally, the P-R group also exhibited increased helper T cell diapedesis, cytotoxic T cell differentiation pathways, and stimulatory C-type lectin receptor signaling pathways.

Similar enriched pathways, as well as enhanced CD8 + T-cell activation and Th2 differentiation pathways, were seen in the R-P group. Increased modulation of the dendritic cell pathway, innate immune response signaling, Th2, and cytotoxic T-cell differentiation pathways was seen in the R-R group.

Additionally, it was seen to exhibit enhanced expression of interferon regulatory factor 1 (Irf1), V-set immunoregulatory receptor, and Bcl6, which is a transcription factor for follicular helper T-cells and Hmgb1.

Furthermore, no discernible difference between the homologous and heterologous prime-boost regimens’ protective effect was found. The P-R group showed minimal to mild lung alterations, whereas the R-P group showed mild to moderate abnormalities. One week after the viral challenge, the viral titers in the BALF and lungs were seen to be lower in the R-P group compared to the P-R group. IgG2a concentrations were found to be greater in the P-R group than in the R-P group.

Larger percentages of CD4 + T cells that produce IL-2, TNF-, and IFN- were seen in the R-P group, whereas higher percentages of CD8 + T cells that produce IL-2, TNF-, and IFN- were seen in the P-R group. Additionally, it was shown that the R-P group had the lowest levels of central CD8 + T cells as well as proliferating effectors CD4 + and CD8 + T cells after the viral challenge.

Therefore, the current work implies that the most efficient and secure immunization method against the virus may involve a heterologous vaccination strategy that includes an initial inoculation with an mRNA vaccine followed by a secondary or tertiary inoculation with a protein vaccine.

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