A paper in Cell in September 2024 presents a promising mRNA vaccine candidate against mpox disease. The mRNA-lipid nanoparticle (LNP) vaccine expresses MPXV surface proteins and was compared with modified vaccinia Ankara (MVA) vaccine, proving to confer protection against challenge and mitigate symptoms and disease duration. Furthermore, it provided “enhanced viral control and disease attenuation” compared to MVA, which highlights the potential of mRNA vaccines against future pandemic threats.
A new modality
Despite the availability of an effective vaccine against mpox, the authors note “issues in supply, unfavourable reactogenicity, incomplete immunity, and uncertainty of cross-protection”. These factors provide “critical motivation” for the pursuit of a new vaccine modality for “improved vaccines to cover these gaps”. mRNA vaccines offer “unprecedented flexibility, speed, and immunogenicity”. However, it was unclear whether an mRNA vaccine could provide “comparable immune protection” to a whole attenuated poxviral vaccine vector.
The study
The authors used a stringent clade I MPXV Zaire 1979 (Z79) MPXV nonhuman primate (NHP) model to assess the protective efficacy of mRNA-1769, an mRNA-lipid nanoparticle (LNP) vaccine. It expresses optimised versions of four antigens of interest (A29, A35, B6, and M1). This vaccine was compared with mRNA; both vaccines were administered in “clinically relevant doses”.
Both vaccines conferred “complete protection” after lethal MPXV challenge. However, mRNA-immunised animals experienced 10-fold fewer lesions, reduced disease duration, and “substantial” mitigation of circulating and mucosal viraemia. Furthermore, deep immunological profiling of the humoral response revealed more robust MPXV neutralising responses, broadly reactive heterologous neutralising titres, and greater functional humoral immune responses against the four antigens in the mRNA-immunised animals.
Immune correlates analyses highlighted the “critical coordination” between neutralising and Fc-effector functions against both EV and MV targets, EV-Fc target-specific functions and neutralisation as key correlates of antiviral control, and EV target-antigen-specific opsonophagocytic activity and neutrophil/natural killer cell-targeted functions to the MV as “key determinants” of lesional control. These results suggest that the mRNA-LNP vaccine induced a robust functional humoral response that provided protection against a lethal MPXV challenge. This is like MVA immunisation but with the benefit of “superior protection against disease”.
“These data provide critical insights into mRNA-vaccine-induced correlates of immunity against MPXV, which can support licensure, provide mechanistic insights on vaccine performance, support optimised vaccine usage in vulnerable populations, and inspire redesign should novel Orthopoxviral threats emerge requiring antigen addition or alteration.”
Rapid responses
The authors reflect on the “lack of vaccine deployment and access to medical countermeasures”, which has “fuelled the spread” of mpox from “traditionally endemic rural areas” to larger metropolitan centres. They suggest that lack of routine immunisation with contemporary VACV-based vaccines has provided “fertile ground” for low-level spread of the virus and opportunities for mutation.
“Thus, additional safe and highly efficacious vaccine platforms that are rapidly adaptable upon viral mutation are urgently needed.”
Nucleic-acid vaccines, like mRNA-LNP vaccine technologies, facilitate rapid responses to emerging viral threats. Sequences against key genes can be synthesised and converted into a potential vaccine quickly, and production can take place at regions of interest through worldwide manufacturing centres.
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