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Developing a vaccine against infectious disease isn’t always straightforward. While many injectable vaccinations are highly effective, growing research has identified that targeted vaccination to the primary affected tissues may be both more effective and longer lasting.

Genital herpes, caused by herpes simplex virus 2 (HSV-2), is notoriously difficult to effectively vaccinate against due to the immunosuppressive nature of the vaginal mucosal lining, which reduces the effectiveness of vaccines through reduced immune priming.

Previous research shows that CpG oligodeoxynucleotides (ODNs), a synthetic DNA molecule, is effective at stimulating the immune system and reduce viral loads when delivered intravaginally. While effective, this method often results in significant inflammation of the mucosa.

Researchers at Yale University published a study in Science Immunology in which they explain a new strategy to improving the protective ability of an HSV-2 vaccine while reducing the inflammatory side effects. Their approach combines a vaccine adjuvant to stimulate the immune system by recruiting T cells with ODNs.

“Effective local immunity, mediated in part by tissue-resident memory T cells (TRM cells) and luminal antibodies, provides immediate viral control,” wrote the authors. They tested the ability of chemokines bound to ODNs to improve vaccine specificity and efficiency in vaginal mucosa. Their technique is celled bioactive enhanced adjuvant chemokine oligonucleotide nanoparticles (BEACONs).

“Systemically primed immunity can be leveraged to generate appropriate mucosal responses,” the authors reasoned. “For example, intramuscular priming [can] establish a pool of antigen-specific T and B cells, followed by a mucosal boost to drive their recruitment to and activation at the site of infection.”

Using a mouse model, the team tested the adjuvant which combined the CpG ODNs with CXCL9. The mice were initially dosed with an intramuscular injection of HSV-2 glycoprotein-encoding messenger RNA–lipid nanoparticles, followed by an intravaginal booster containing the cognate recombinant glycoprotein and BEACONs.

While additional chemokines were tested, including CXCL10 and a truncated version of CXCL9, neither was effective. “These data emphasize the structural features of the chemokine component that directly influence particle formation and immunological function,” wrote the authors.

BEACONs were shown to improve uptake of ODNs by antigen presenting cells and promoted the recruitment and retention of HSV-specific CD8 T cells in the vaginal mucosa. However, this effect was only seen in the combination treatment. “This response was not induced by CXCL9 or CpG ODNs alone, nor was it observed after intramuscular boosting, indicating that both local antigen and adjuvant signals are required to establish durable CD8 TRM cell populations,” they wrote.

“Our data support a model in which mucosal boosting primarily leads to recruitment and local reprogramming of systemically primed effectors rather than driving a second systemic expansion.”

These data suggest that not only is this technique effective in vaccinating against HSV-2, but there are broader implications to this technique. They explored the concept of delivering a vaccination dose for systemic priming followed by localized delivery of the vaccine components combined with an adjuvant to amplify relevant effectors at infection sites. Further, they highlighted how use of nanoparticle formulations can help to fine-tune reactogenicity of CpG ODNs to reduce inflammation responses, which would be helpful for clinical translation.

“Our findings offer a generalizable strategy for targeting other sexually transmitted pathogens, including HIV-1, human papillomavirus, and chlamydia, in which mucosal immunity is essential but poorly induced by [other types of] vaccines,” the authors wrote.

While these results are promising, more work is needed to establish the long-term efficacy of the strategy by testing viral shedding and testing in alternate models, and multiple delivery methods to adapt for self-administration or clinical options for dose delivery.

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