T cells are ready for the fight against monkeypox

Abstract

In this issue of Cell Host & Microbe, Grifoni et al. provide reassuring evidence that the majority of epitopes induced by vaccinia virus vaccines are conserved in monkeypox virus and can elicit memory T cell responses, while also providing an extensive list of potential T cell epitopes.

In this issue of Cell Host & Microbe, Grifoni et al. provide reassuring evidence that the majority of epitopes induced by vaccinia virus vaccines are conserved in monkeypox virus and can elicit memory T cell responses, while also providing an extensive list of potential T cell epitopes.

Main text

While the world’s focus was on SARS-CoV-2, another viral pathogen was gaining traction—monkeypox virus (MPXV). Since it was first identified in 1970, MPXV has become endemic in Africa but is rarely seen in other continents. The recent outbreak has now spread to more than 95 countries and infected more than 75,000 people. Despite this high prevalence of infections, the number of confirmed deaths remains low at 36 worldwide.

Very few studies into the immune responses associated with natural infection exist. Vaccines based on vaccinia virus (VACV) or modified vaccinia virus Ankara, which were designed to protect against smallpox virus, have been successfully used to protect against MPXV, with efficacy rates of 85%.¹ However, the immunity induced by these vaccines against MPXV has not been thoroughly characterized. This is largely due to their large viral genome sizes, ranging from 130 to 300 kb, with more than 200 open reading frames (ORFs).² T cell responses to infection are an integral part of the host’s ability to fight viruses. Most T cell studies have focused on responses to VACV, as these are the basis of vaccines against orthopoxviruses.^{3 , 4} While epitopes have been identified, understanding a hierarchy of immunodominance for these has been difficult, particularly due to the large number of antigens potentially available from the virus.⁵

In this issue, Grifoni et al.⁶ present a timely and important study into the cross-reactivity of T cells to MPXV and VACV, which share 90% sequence homology. They created mega peptide pools based on publicly available data on confirmed orthopoxvirus epitopes and then compared how these epitope sequences related with MPXV regions, concluding that 94% of CD4 and 82% of CD8 epitopes were present in the MPXV sequence. This shared homology suggests that there will be strong cross-reactivity of T cells primed by VACV to MPXV. However, while there may be homology in the epitope sequence, the sequence of the epitope-flanking regions may also affect whether epitopes are actually presented at the cell surface.^{7 , 8} The authors next confirmed that these mega peptide pools can stimulate memory T cell responses by investigating the responses of donors previously vaccinated with the Dryvax VACV vaccine.

As orthopoxviruses generally have around 200 ORFs, Grifoni et al. further these studies by narrowing down the ORFs that generate the majority of epitopes (≥5). From the subsequent list of 19 CD4 and 40 CD8 candidates, and subsequent cross-referencing with only those epitopes homologous in MPXV, they created a second set of mega peptide pools of in silico predicted MPXV epitopes, which were subsequently shown to activate T cell responses. While this generated a large pool of potential immunodominant epitopes for MPXV that will be invaluable to the field moving forward, the use of only common HLA (human leukocyte antigen) alleles may result in the absence of additional key epitopes presented by non-common HLA alleles. Therefore, it is important that future studies include donors with less common HLA types, as there may be a whole raft of dominant epitopes that we have yet to identify.

While this study is an excellent starting point, closer investigations are required to identify specific immunodominant MPXV epitopes that stimulate long-lasting T cell responses. In addition, the saturating concentration of exogenous pooled peptides may not be able to fully represent overall T cell responses to virus-infected cells and their anti-viral efficacy. The concentration of each epitope on the surface of infected cells may vary due to the efficiency of antigen processing and their presentation by individual HLA molecules. Future studies should consider combining exogenous peptides with systems such as vaccinia.^{9 , 10} These systems allow epitopes to be naturally processed and presented, more accurately representing physiological conditions. However, due to the nature of these systems, the T cell responses seen may be lower or less sensitive due to the additional complications that virus infection brings.

Although the correlates of protection are still being defined, what is reassuring about these results is that the use of VACV- or MVA-based vaccines should continue to be largely protective against MPXV disease. While this is positive, there is still the question of whether protection can be improved through the development of better vaccines. To do that, we need better understanding of the T cell responses, including those suggested here, as well as other elements of immunity. Considering the high homology of MPXV and VACV, we must still remember that even a 10% difference in sequence may be sufficient to alter the pool of peptides that actually induce robust and long-lasting T cell responses. Using the information provided here, we can now start to build a clear picture of T cell immune responses to MPXV (Figure 1 ).

Figure 1.

Investigation into monkeypox T cell responses in VACV-vaccinated donors

Grifoni et al. investigate the homology of confirmed human orthopox virus epitopes and T cell responses to these epitopes by donors previously vaccinated with the Dryvax VACV-based vaccine. They also used in silico prediction to identify potential MPXV epitopes from immunodominant ORFs—i.e., those ORFs with 5 or more confirmed epitopes from all human orthopoxviruses. What was not investigated here was the T cell response in systems that consider the natural antigen processing and presentation of the virus. Created with https://biorender.com/.