Monkeypox-Induced Immunity and Failure of Childhood Smallpox Vaccination To Provide Complete Protection

Abstract

In 2003, a zoonotic outbreak of human monkeypox occurred in North America. The outbreak was the first time that this virus caused human disease outside Africa. Subsequent investigation confirmed that the source of the outbreak was an imported consignment of African mammals from the West African nation of Ghana. Subsequently, the virus moved to captive native North American species, including Cynomys species (prairie dogs) (10,21,23). Human cases were infected through contact with infected animals, principally prairie dogs (19,23). Viral isolates associated with the outbreak were genetically characterized as West African variants of monkeypox distinct from Central African viruses (20). During the outbreak, and in a follow-up study, specimens from suspected cases and their contacts were submitted to the Centers for Disease Control and Prevention (CDC) for laboratory testing. Laboratory testing included virological testing (culture and PCR) of presumptive virus-containing specimens for case confirmation and analysis of immunological markers from blood or serum samples. Immunological analysis included serologic testing for orthopoxvirus (OPX)-specific antibodies (immunoglobulin G [IgG] and IgM) and virus-specific cellular (CD4, CD8, and B-cell) immunity evaluation in cases and contacts.In this study, we evaluated human monkeypox cases and household contacts of monkeypox-infected animals and report the characterization of the convalescent and long-term memory (1-year) immune response to monkeypox infection during this outbreak. Correlations between immunological markers, smallpox vaccination status, and infection outcomes are evaluated, as well as memory immune responses in previously vaccinated individuals within this cohort. MATERIALS AND METHODS Specimens.Response to the 2003 U.S. monkeypox outbreak involved the collection of information related to lab results, exposure characteristics, clinical features of illness, and other epidemiologic features. Teams of clinicians, epidemiologists, and microbiologists from the CDC and the six affected states collected information and samples from cases and contacts of cases. Patient specimens were sent to the CDC as a part of the outbreak investigation, and confirmation of suspect cases was based on identification of virus in tissuederived specimens (21). As an extension of the outbreak investigation, a followup, household-based, Institutional Review Board-approved, case control study was initiated to assess exposures, clinical markers of disease severity, and immune responses at 7 to 14 weeks (convalescent) and at 1 year postexposure. Specimens were collected at convalescent and 1-year time points, and clinical and epidemiologic information was collected with a standardized questionnaire. A total of 92 persons enrolled in the study. Eighteen of those enrolled were excluded from the analysis due to unknown vaccination status or unwillingness to provide biological samples. A total of 72 individuals were considered in these analyses. Enrolled individuals were categorized into ...

Retrospective Analysis of Monkeypox Infection

“…A more recent study identifi ed 3 unvaccinated contacts who were negative by IgM ELISA but positive by IgG ELISA despite no reported disease symptoms (10). If these contacts contracted monkeypox infections, then this would contradict our previous fi ndings in which unvaccinated monkeypox patients showed at least some, if not all, disease symptoms associated with monkeypox (6,8).…”

“…If these contacts contracted monkeypox infections, then this would contradict our previous fi ndings in which unvaccinated monkeypox patients showed at least some, if not all, disease symptoms associated with monkeypox (6,8). It is diffi cult to directly compare our results with these other reports (10,29) because different subsets of monkeypox patients were examined, different time points were analyzed, and different case defi nitions were used. For instance, the CDC case defi nition is based on a combination of clinical, Figure 3.…”

“…These symptoms can also vary among persons; most American patients in the 2003 monkeypox outbreak had a rash with 1 to >100 skin lesions (4-7), whereas others had monkeypox infection without exanthem (8,9). Moreover, adults with preexisting immunity from childhood smallpox vaccinations may experience milder symptoms (5,10) or no symptoms (6). Standard clinical algorithms (11,12) may fail to identify these mild or asymptomatic cases; likewise, they are diffi cult to confi rm by virologic methods because of the absence of skin lesions.…”

Antiviral Immunity following Smallpox Virus Infection: a Case-Control Study

“…Although several studies have examined the duration of immunity following smallpox vaccination (2,4,9,17,31,35), little is known about the magnitude or duration of immunity following natural smallpox infection itself (32,35). This is an important question because smallpox infection is believed to confer lifelong protective immunity (5), whereas protective immunity following smallpox vaccination represents a topic of considerable debate; protective immunity is either long-lived (2,9,10,15,17,31,33,35) or may persist for only 3 to 5 years (19,21,26,28).…”

The TNFR family members OX40 and CD27 link viral virulence to protective T cell vaccines in mice

“…These include modified VACV Ankara (MVA) (14), a variant of Lister strain LC16m8; ACAM1000/2000, derived from New York City Board of Health strain NYCBOH; the highly deleted Copenhagen VACV strain derivative NYVAC; and attenuated canarypox virus (ALVAC). Although some vectors given by certain routes might result in strong CD8 + T cell responses, the literature also suggests there is variability in the levels of CD8 + T cell immunity, raising the question of what determines induction of optimal CD8 + T cell responses (2,(7)(8)(9)(10)(15)(16)(17). Using several clinically relevant natural and recombinant VACV variants, we show here a quantitative difference in CD8 + T cell immunity elicited depending on the virus and immunization route, with only the most virulent VACVs promoting protective populations of memory CD8 + T cells.…”