Monkeypox-induced immunity and failure of childhood smallpox vaccination to provide complete protection

Abstract

Following the U.S. monkeypox outbreak of 2003, blood specimens and clinical and epidemiologic data were collected from cases, defined by standard definition, and household contacts of cases to evaluate the role of preexisting (smallpox vaccine-derived) and acquired immunity in susceptibility to monkeypox disease and clinical outcomes. Orthopoxvirus-specific immunoglobulin G (IgG), IgM, CD4, CD8, and B-cell responses were measured at approximately 7 to 14 weeks and 1 year postexposure. Associations between immune responses, smallpox vaccination, and epidemiologic and clinical data were assessed. Participants were categorized into four groups: (i) vaccinated cases, (ii) unvaccinated cases, (iii) vaccinated contacts, and (iv) unvaccinated contacts. Cases, regardless of vaccination status, were positive for orthopoxvirus-specific IgM, IgG, CD4, CD8, and B-cell responses. Antiorthopoxvirus immune responses consistent with infection were observed in some contacts who did not develop monkeypox. Vaccinated contacts maintained low levels of antiorthopoxvirus IgG, CD4, and B-cell responses, with most lacking IgM or CD8 responses. Preexisting immunity, assessed by high antiorthopoxvirus IgG levels and childhood smallpox vaccination, was associated (in a nonsignificant manner) with mild disease. Vaccination failed to provide complete protection against human monkeypox. Previously vaccinated monkeypox cases manifested antiorthopoxvirus IgM and changes in antiorthopoxvirus IgG, CD4, CD8, or B-cell responses as markers of recent infection. Antiorthopoxvirus IgM and CD8 responses occurred most frequently in monkeypox cases (vaccinated and unvaccinated), with IgG, CD4, and memory B-cell responses indicative of vaccine-derived immunity. Immune markers provided evidence of asymptomatic infections in some vaccinated, as well as unvaccinated, individuals.

FIG. 1.

ELISA of anti-OPX IgM responses in convalescent and 1-year sampling of all cases and contacts based on vaccination status. Results are presented as OD − COV where values above zero are considered positive. IgM values of 0 to 0.04 are considered equivocal. Symbols represent individuals involved in the study and remain consistent throughout the figures.

FIG. 2.

ELISA of anti-OPX IgG responses in convalescent and 1-year sampling of all cases and contacts based on vaccination status. Results are presented as OD − COV where values above zero are considered positive. Symbols represent individuals involved in the study and remain consistent throughout the figures.

FIG. 3.

Detection of OPX-specific T-cell memory responses in convalescent and 1-year sampling of cases and contacts. The limit of detection for this assay was 0.01% (red dashed line). Symbols represent individuals involved in the study and remain consistent throughout the figures.

FIG. 4.

Detection of OPX-specific B-cell memory responses in convalescent and 1-year sampling of cases and contacts. The limits of detection for these assays were 0.01% (a) and 0.004% (b) (dashed red line in both panels). Symbols represent individuals involved in the study and remain consistent throughout the figures.

FIG. 5.

Distribution of anti-OPX immune responses in monkeypox cases differentiated by disease severity as mild or moderate/severe, as described in Materials and Methods. (a) IgM (within 4 weeks post-rash onset); (b) IgG (4 weeks post-rash onset); (c) CD4 (convalescent sampling); (d) CD8 (convalescent sampling); (e) memory B cells (convalescent sampling). Symbols represent individuals involved in the study and remain consistent throughout the figures.