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The kinetics of T cell response, the inflammatory profile, and the pox-specific T cell induction in monkeypox infection

The recent outbreak of monkeypox among humans in several developed countries where the virus was previously not known to be endemic roused fears that this might lead to the next pandemic. A new study, posted on Preprints with The Lancet*, describes the changes in immune T cell profile over time following monkeypox infection.


At present, nearly 50,000 cases of human monkeypox have been reported worldwide. The current outbreak shows some significant differences from earlier outbreaks in West and Central Africa, such as the appearance of lesions over a longer period and a much higher proportion of lesions in the anogenital area. Moreover, well above 90% of the patients were men who have sex with men (MSM).

History of smallpox vaccination confers 85% protective immunity against monkeypox, though this is limited to those aged 40 years or above. CD8 T cells appear to play a major role in the cellular immune response to the monkeypox virus. All convalescent cases develop virus-specific IgM, IgG, B and T cell responses.

While in most cases, infection is followed by clinical signs and symptoms, a small number appear to develop a subclinical infection. Specific cytokines appear excessively produced in a few patients who develop serious disease.

In the current outbreak, over 40% were people living with HIV (PLWH) infection, which may impact the immune response.

The current study aimed to explore the T cell response and the inflammatory reaction to the monkeypox infection. The study sample was very small, comprising 17 patients, all MSM with a median age of 39 years, HIV being present in 7 individuals. In all 7, the HIV was undetectable, and the CD4 T cell count was normal, all being on antiretroviral therapy. Of the rest, most were on pre-exposure prophylaxis (PrEP).

Most of the patients said they might have been infected by sexual contact. Five received an antiviral against the monkeypox virus. Only one had a history of prior smallpox vaccination.

What did the study show?

During the first 3 days post-infection, CD4 T cells were markedly reduced while CD8 T cells increased in proportion. Both CD4 and CD8 T cells mostly showed the effector memory cell phenotype, with reduced frequency of naïve cells, indicating active engagement with the virus. Over time, the relative proportions normalized.

These changes appeared independent of the HIV status, indicating preservation of the immune response. These responses occurred mostly in those with more or larger lesions and systemic symptoms.

Inflammatory cytokines such as certain interleukins (ILs), including IL-1β, IL-6, IL-8, and the tumor necrosis factor TNF, were present at higher concentrations in monkeypox patients than in controls, persisting throughout the period of active infection and even into the convalescent stage, though at this point their levels were reduced. These cytokines were strongly correlated with each other.

Between days 8 and 10, after the acute phase, activated CD4 T cells and senescent CD8 T cells formed a higher proportion of the total. The latter form part of a population of terminally differentiated effector memory T-cells re-expressing CD45RA (EMRA) and express senescent marker (CD57), while others express the activation marker (PD1).

When stimulated by monkeypox virus pooled peptides, peripheral blood mononuclear cells (PBMCs) showed a poxvirus-specific T cell response in almost every case. The strength of the specific T cell response was independent of the clinical features. However, cytokine levels varied with the severity of symptoms.

What are the conclusions?

Monkeypox infection in naïve human subjects appears to produce a strong immune response, characterized by the reduction of naïve CD4 and CD8 T cells, with the rapid expansion of both CD4 and CD8 T effector memory cells expressing surface markers CD38, PD-1, and CD57. This level of activation decreased as the patient recovered.

Most patients had increased inflammatory cytokine concentrations produced by virus-specific T cells soon after the onset of symptoms. The raised levels persisted into the convalescent period. Mild infections were associated with a lower level of T cell activation and differentiation.

The strong T cell cytokine response to viral antigens at 10-12 days from symptom onset appears independent of symptoms. Even though the monkeypox virus evades T cell recognition, other immune mechanisms allow the human host to mount antiviral T cell responses rapidly and potently, often better than following exposure to the vaccinia virus.

After an earlier monkeypox outbreak (the USA, 2003), survivors showed persistent, robust cell-mediated immunity against the virus for at least one year, indicating that memory CD4 T cells continued to persist after natural infection. This resembles the responses to smallpox vaccination, an important finding since CD4 T cell memory cells provide a continuing stimulus for prolonged B cell memory.

The currently circulating virus clade is very similar to the West Africa clade and appears to evoke an early immune-inflammatory response, indicating protective innate immune responses at work. This may explain the preponderance of mild infections.

The perturbation of adaptive cellular immunity by HIV infection did not appear to curtail the rapid, effective response to monkeypox, though all such patients in this study had well-controlled HIV. This corroborates other research showing that HIV does not affect the presentation or severity of monkeypox. Moreover, it suggests that monkeypox vaccines may be equally effective in PLWH.

Further work should be addressed to patients with advanced HIV disease who presumably have a lower cellular immune capacity.

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