Humoral and T-cell-mediated responses to a pre-clinical Zika vaccine candidate that utilizes a unique insect-specific flavivirus platform

Background

Zika virus (ZIKV) is a mosquito-borne illness that is a significant threat to human health. It is especially dangerous when it is passed from mother to fetus because infection can cause severe birth defects. Currently there is neither a vaccine nor a specific treatment for ZIKV, despite the global burden of disease and the extended length of time since its discovery. One of the main concerns when developing a vaccine is balancing immunogenicity with safety. The authors of this preprint used an Aripo virus (ARPV) backbone to build a recombinant vaccine. This virus was isolated from mosquitoes and is specific to insects. Because of this insect host specificity, the vaccine backbone is non-pathogenic in vertebrates and cannot revert to a pathogenic form. Therefore, it is extremely safe. Previous work had found that a single dose of this ARPV/ZIKV vaccine completely protected mice from viremia, death, and even in utero transmission of ZIKV, partly due to high neutralizing antibody titers.

Summary

Humoral and cellular immunity soon after vaccination

The work described in this preprint builds on previous work that found that a dose of the ARPV/ZIKV vaccine protected mice from ZIKV challenge. The main goal now was to better understand both the humoral and cellular immune responses to the vaccine. First, the researchers tested passive antibody transfer by injecting sera containing neutralizing antibodies into mice. However, this conferred only partial protection against ZIKV challenge.

This observation led to the hypothesis that cellular immunity is involved in host protection, but when the authors challenged vaccinated T-cell depleted mice with ZIKV, they did not experience significantly greater mortality than vaccinated mice with functional T cells. The authors also took T cells from vaccinated mice and inoculated them into naïve mice before challenging them with ZIKV. These animals survived an average of two days longer than mock inoculated animals and also lost less weight. These two experiments indicated that the T-cell response was minor compared to the neutralizing antibody response.

Cellular immunity post-vaccination

The experiments described above all involved challenge with ZIKV relatively soon after vaccination. The researchers decided to see whether a T-cell response was found in the development of post-vaccination immune response. To this end they vaccinated mice without functional T cells (Tcra KO), without B cells (muMt^–), and without either T or B cells (Rag1 KO). In this experiment, the authors waited to give the mice a lethal challenge with ZIKV until 30 days post vaccination. Challenge with ZIKV had no effect on the muMt^– mutant but affected both other mutants, indicating that the T-cell response is critical in the development of long-term immunity after vaccination.

Conclusion

Overall, the researchers found that vaccination with ARPV/ZIKV in the short term resulted in massive neutralizing antibody response and that the depletion of T cells did not impact survival. This indicates that a T-cell response in this case is not as important as the neutralizing antibodies, and a proper adjuvant should be considered in future vaccines to stimulate T-cell activity. However, when longer-term immunity was considered, cells that were deficient in B cells but did have T-cell activation survived longer than other mutants, indicating that the T-cell response is critical to the development of long-term immunity.

What I liked about this preprint

I thought that the concept of using an insect-specific virus backbone for a recombinant vaccine was fascinating due to the potential overcoming of safety concerns. I would like to see whether this concept can be applied to other viruses as well.

Questions for the authors

1. Have you considered experimenting with a prime-boost regimen to increase T-cell activation at the time of vaccination?
2. Have you tested these neutralizing antibodies for cross-reactivity with other flaviviruses?
3. What is your hypothesis as to why the neutralizing antibodies did not provide complete protection to ZIKV challenge if there was no significant T-cell response?
4. In Figure 1, the upregulation of gene expression associated with IFN-γ, NF-κB, and TLR signaling was shown. However, this experiment was done in macrophages, which use these signaling pathways to enhance their phagocytic response to antigens. Will you be doing future experiments to directly correlate the upregulation of these pathways to T-cell activation?

Tags: cellular immunity, humoral immunity, vaccine development

doi: https://doi.org/10.1242/prelights.34233

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