Predicting vaccine effectiveness for mpox.

The Modified Vaccinia Ankara vaccine developed by Bavarian Nordic (MVA-BN) was widely deployed to prevent mpox during the 2022 global outbreak. This vaccine was initially approved for mpox based on its reported immunogenicity (from phase I/II trials) and effectiveness in animal models, rather than evidence of clinical efficacy. However, no validated correlate of protection after vaccination has been identified. Here we performed a systematic search and meta-analysis of the available data to test whether vaccinia-binding ELISA endpoint titer is predictive of vaccine effectiveness against mpox. We observe a significant correlation between vaccine effectiveness and vaccinia-binding antibody titers, consistent with the existing assumption that antibody levels may be a correlate of protection. Combining this data with analysis of antibody kinetics after vaccination, we predict the durability of protection after vaccination and the impact of dose spacing. We find that delaying the second dose of MVA-BN vaccination will provide more durable protection and may be optimal in an outbreak with limited vaccine stock. Although further work is required to validate this correlate, this study provides a quantitative evidence-based approach for using antibody measurements to predict the effectiveness of mpox vaccination.

Levels of antibodies against the monkeypox virus compared by HIV status and historical smallpox vaccinations: a serological study.

Men who have sex with men and people living with HIV are disproportionately affected in the 2022 multi-country monkeypox epidemic. The smallpox vaccine can induce cross-reactive antibodies against the monkeypox virus (MPXV) and reduce the risk of infection. Data on antibodies against MPXV induced by historic smallpox vaccination in people with HIV are scarce. In this observational study, plasma samples were collected from people living with and without HIV in Shenzhen, China. We measured antibodies binding to two representative proteins of vaccinia virus (VACV; A27L and A33R) and homologous proteins of MPXV (A29L and A35R) using an enzyme-linked immunosorbent assay. We compared the levels of these antibodies between people living with and without HIV. Stratified analyses were performed based on the year of birth of 1981 when the smallpox vaccination was stopped in China. Plasma samples from 677 people living with HIV and 746 people without HIV were tested. A consistent pattern was identified among the four antibodies, regardless of HIV status. VACV antigen-reactive and MPXV antigen-reactive antibodies induced by historic smallpox vaccination were detectable in the people born before 1981, and antibody levels reached a nadir during or after 1981. The levels of smallpox vaccine-induced antibodies were comparable between people living with HIV and those without HIV. Our findings suggest that the antibody levels against MPXV decreased in both people living with and without HIV due to the cessation of smallpox vaccination.

JYNNEOS Vaccine for Mpox.

This JAMA Patient Page describes the eligibility, safety and effectiveness, and administration procedure for the JYNNEOS vaccine for mpox infection.

Effectiveness of JYNNEOS Vaccine Against Diagnosed Mpox Infection - New York, 2022.

In 2022, an international Monkeypox virus outbreak, characterized by transmission primarily through sexual contact among gay, bisexual, and other men who have sex with men (MSM), resulted in 375 monkeypox (mpox) cases in the state of New York outside of New York City (NYC).*,† The JYNNEOS vaccine (Modified Vaccinia Ankara vaccine, Bavarian Nordic), licensed by the U.S. Food and Drug Administration (FDA) against mpox as a 2-dose series, with doses administered 4 weeks apart,§ was deployed in a national vaccination campaign.¶ Before this outbreak, evidence to support vaccine effectiveness (VE) against mpox was based on human immunologic and animal challenge studies (1-3). New York State Department of Health (NYSDOH) conducted a case-control study to estimate JYNNEOS VE against diagnosed mpox in New York residents outside of NYC, using data from systematic surveillance reporting. A case-patient was defined as a man aged ≥18 years who received a diagnosis of mpox during July 24-October 31, 2022. Contemporaneous control patients were men aged ≥18 years with diagnosed rectal gonorrhea or primary syphilis and a history of male-to-male sexual contact, without mpox. Case-patients and control patients were matched to records in state immunization systems. JYNNEOS VE was estimated as 1 - odds ratio (OR) x 100, and JYNNEOS vaccination status (vaccinated versus unvaccinated) at the time of diagnosis was compared, using conditional logistic regression models that adjusted for week of diagnosis, region, patient age, and patient race and ethnicity. Among 252 eligible mpox case-patients and 255 control patients, the adjusted VE of 1 dose (received ≥14 days earlier) or 2 doses combined was 75.7% (95% CI = 48.5%-88.5%); the VE for 1 dose was 68.1% (95% CI = 24.9%-86.5%) and for 2 doses was 88.5% (95% CI = 44.1%-97.6%). These findings support recommended 2-dose JYNNEOS vaccination consistent with CDC and NYSDOH guidance.

Demographics and Health Beliefs of Black Gay, Bisexual, and Other Sexual Minority Men Receiving a Mpox Vaccination in the United States.

An outbreak of mpox virus (MPV) among humans in the United States (U.S.) was described in May 2022. This outbreak disproportionately affects Black and Hispanic sexual minority men (SMM) and these groups have lower rates of vaccination compared to Whites. Between July and August 2022, a partnership between a nonprofit and two local health departments successfully designed and implemented a community intervention to administer MPV vaccines to Black SMM in the Washington D.C. metropolitan area. We administered a quantitative survey to 178 respondents across four vaccinations clinics. We found that study participants had high socioeconomic status, high levels of anticipated MPV stigma, and were relatively skeptic about MPV. We demonstrated how a partnership between an urban nonprofit and government agency can facilitate quick and effective dissemination of a community intervention in a relatively low cost manner.

Safety Monitoring of JYNNEOS Vaccine During the 2022 Mpox Outbreak - United States, May 22-October 21, 2022.

JYNNEOS (Modified Vaccinia Ankara vaccine, Bavarian Nordic) is recommended in the United States for persons exposed to or at high risk for exposure to Monkeypox virus during the 2022 monkeypox (mpox) outbreak (1). JYNNEOS is a live, nonreplicating viral vaccine licensed for the prevention of smallpox and mpox in adults aged ≥18 years, administered as a 0.5-mL 2-dose series given 28 days apart by subcutaneous injection (2). On August 9, 2022, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for administration of 0.1 mL doses by intradermal injection for adults aged ≥18 years as a strategy to increase vaccine supply, and administration of 0.5 mL doses subcutaneously for persons aged <18 years (3). During May 22-October 21, 2022, a total of 987,294 JYNNEOS vaccine doses were administered in the United States. CDC has monitored JYNNEOS vaccine safety using the Vaccine Adverse Event Reporting System (VAERS) and the Vaccine Safety Datalink (VSD) for vaccine recipients of all ages, and through single-patient emergency Investigational New Drug (EIND) procedures for persons aged <18 years vaccinated before August 9, 2022. The most common adverse health events reported to VAERS for adults were nonserious and included injection site reactions, which was consistent with the prelicensure studies. Adverse health events were reported at similar rates for doses received by intradermal and subcutaneous administration. Serious adverse events were rare in adults, and no serious adverse events have been identified among persons aged <18 years. Overall, postlicensure and postauthorization surveillance to date support JYNNEOS vaccine safety.

Reduced Risk for Mpox After Receipt of 1 or 2 Doses of JYNNEOS Vaccine Compared with Risk Among Unvaccinated Persons - 43 U.S. Jurisdictions, July 31-October 1, 2022.

As of October 28, 2022, a total of 28,244* monkeypox (mpox) cases have been reported in the United States during an outbreak that has disproportionately affected gay, bisexual, and other men who have sex with men (MSM) (1). JYNNEOS vaccine (Modified Vaccinia Ankara vaccine, Bavarian Nordic), administered subcutaneously as a 2-dose (0.5 mL per dose) series (with doses administered 4 weeks apart), was approved by the Food and Drug Administration (FDA) in 2019 to prevent smallpox and mpox disease (2); an FDA Emergency Use Authorization issued on August 9, 2022, authorized intradermal administration of 0.1 mL per dose, increasing the number of persons who could be vaccinated with the available vaccine supply† (3). A previous comparison of mpox incidence during July 31-September 3, 2022, among unvaccinated, but vaccine-eligible men aged 18-49 years and those who had received ≥1 JYNNEOS vaccine dose in 32 U.S. jurisdictions, found that incidence among unvaccinated persons was 14 times that among vaccinated persons (95% CI = 5.0-41.0) (4). During September 4-October 1, 2022, a total of 205,504 persons received JYNNEOS vaccine dose 2 in the United States.§ To further examine mpox incidence among persons who were unvaccinated and those who had received either 1 or 2 JYNNEOS doses, investigators analyzed data on 9,544 reported mpox cases among men¶ aged 18-49 years during July 31-October 1, 2022, from 43 U.S. jurisdictions,** by vaccination status. During this study period, mpox incidence (cases per 100,000 population at risk) among unvaccinated persons was 7.4 (95% CI = 6.0-9.1) times that among persons who received only 1 dose of JYNNEOS vaccine ≥14 days earlier and 9.6 (95% CI = 6.9-13.2) times that among persons who received dose 2 ≥14 days earlier. The observed distribution of subcutaneous and intradermal routes of administration of dose 1 among vaccinated persons with mpox was not different from the expected distribution. This report provides additional data suggesting JYNNEOS vaccine provides protection against mpox, irrespective of whether the vaccine is administered intradermally or subcutaneously. The degree and durability of such protection remains unclear. Persons eligible for mpox vaccination should receive the complete 2-dose series to optimize strength of protection†† (5).

Mpox vaccination willingness, determinants, and communication needs in gay, bisexual, and other men who have sex with men, in the context of limited vaccine availability in the Netherlands (Dutch Mpox-survey).

Introduction: In the 2022 multicountry mpox (formerly named monkeypox) outbreak, several countries offered primary preventive vaccination (PPV) to people at higher risk for infection. We study vaccine acceptance and its determinants, to target and tailor public health (communication-) strategies in the context of limited vaccine supply in the Netherlands. Methods: Online survey in a convenience sample of gay, bisexual and other men who have sex with men, including transgender persons (22/07-05/09/2022, the Netherlands). We assessed determinants for being (un)willing to accept vaccination. We used multivariable multinominal regression and logistic regression analyses, calculating adjusted odds ratios (aOR) and 95 percent confidence-intervals. An open question asked for campaigning and procedural recommendations. Results: Of respondents, 81.5% (n = 1,512/1,856) were willing to accept vaccination; this was 85.2% (799/938) in vaccination-eligible people and 77.7% (713/918) in those non-eligible. Determinants for non-acceptance included: urbanization (rural: aOR:2.2;1.2-3.7; low-urban: aOR:2.4;1.4-3.9; vs. high-urban), not knowing mpox-vaccinated persons (aOR:2.4;1.6-3.4), and lack of connection to gay/queer-community (aOR:2.0;1.5-2.7). Beliefs associated with acceptance were: perception of higher risk/severity of mpox, higher protection motivation, positive outcome expectations post vaccination, and perceived positive social norms regarding vaccination. Respondents recommended better accessible communication, delivered regularly and stigma-free, with facts on mpox, vaccination and procedures, and other preventive options. Also, they recommended, "vaccine provision also at non-clinic settings, discrete/anonymous options, self-registration" to be vaccinated and other inclusive vaccine-offers (e.g., also accessible to people not in existing patient-registries). Conclusion: In the public health response to the mpox outbreak, key is a broad and equitable access to information, and to low-threshold vaccination options for those at highest risk. Communication should be uniform and transparent and tailored to beliefs, and include other preventive options. Mpox vaccine willingness was high. Public health efforts may be strengthened in less urbanized areas and reach out to those who lack relevant (community) social network influences.

Vaccine hesitancy and other obstacles to COVID-19 control: lessons from smallpox.

The world confronts today a disease which was unknown as recently as early 2019. Now that there is a safe and effective vaccine against COVID-19, lessons can usefully be drawn from previous well documented vaccination efforts. Of these, the best documented and most successful is the Smallpox Eradication Program (SEP). A review was made of publications by major players in smallpox eradication, respecting the important differences between the disease, this review revealed several points of connection. Cultural factors loomed large both in the eradication of smallpox and progress, to date, in the control of COVID-19. Other points of similarity included political commitment, the set-up of strong surveillance mechanisms, and assurance of uniformly high quality vaccines tested and approved by the World Health Organization. The future of COVID-19 control depends, in part, on lessons learned from previous vaccination efforts. A review of those efforts will avoid repetition of past errors and permit adoption of best practices from the past. Such analyses must, of course, respect the important differences between COVID-19 and smallpox.

A human recombinant analogue to plasma-derived vaccinia immunoglobulin prophylactically and therapeutically protects against lethal orthopoxvirus challenge.

Orthopoxviruses such as variola and monkeypox viruses continue to threaten the human population. Monkeypox virus is endemic in central and western Africa and outbreaks have reached as far as the U.S. Although variola virus, the etiologic agent of smallpox, has been eradicated by a successful vaccination program, official and likely clandestine stocks of the virus exist. Moreover, studies with ectromelia virus (the etiological agent of mousepox) have revealed that IL-4 recombinant viruses are significantly more virulent than wild-type viruses even in mice treated with vaccines and/or antivirals. For these reasons, it is critical that antiviral modalities are developed to treat these viruses should outbreaks, or deliberate dissemination, occur. Currently, 2 antivirals (brincidofovir and tecovirimat) are in the U.S. stockpile allowing for emergency use of the drugs to treat smallpox. Both antivirals have advantages and disadvantages in a clinical and emergency setting. Here we report on the efficacy of a recombinant immunoglobulin (rVIG) that demonstrated efficacy against several orthopoxviruses in vitro and in vivo in both a prophylactic and therapeutic fashion. A single intraperitoneal injection of rVIG significantly protected mice when given up to 14 days before or as late as 6 days post challenge. Moreover, rVIG reduced morbidity, as measured by weight-change, as well as several previously established biomarkers of disease. In rVIG treated mice, we found that vDNA levels in blood were significantly reduced, as was ALT (a marker of liver damage) and infectious virus levels in the liver. No apparent adverse events were observed in rVIG treated mice, suggesting the immunoglobulin is well tolerated. These findings suggest that recombinant immunoglobulins could be candidates for further evaluation and possible licensure under the FDA Animal Rule.

Human Antibody Responses Following Vaccinia Immunization Using Protein Microarrays and Correlation With Cell-Mediated Immunity and Antibody-Dependent Cellular Cytotoxicity Responses.

BACKGROUND: There are limited data regarding immunological correlates of protection for the modified vaccinia Ankara (MVA) smallpox vaccine. METHODS: A total of 523 vaccinia-naive subjects were randomized to receive 2 vaccine doses, as lyophilized MVA given subcutaneously, liquid MVA given subcutaneously (liquid-SC group), or liquid MVA given intradermally (liquid-ID group) 28 days apart. For a subset of subjects, antibody-dependent cellular cytotoxicity (ADCC), interferon-γ release enzyme-linked immunospot (ELISPOT), and protein microarray antibody-binding assays were conducted. Protein microarray responses were assessed for correlations with plaque reduction neutralization titer (PRNT), enzyme-linked immunosorbent assay, ADCC, and ELISPOT results. RESULTS: MVA elicited significant microarray antibody responses to 15 of 224 antigens, mostly virion membrane proteins, at day 28 or 42, particularly WR113/D8L and WR101H3L. In the liquid-SC group, responses to 9 antigens, including WR113/D8L and WR101/H3L, correlated with PRNT results. Three were correlated in the liquid-ID group. No significant correlations were observed with ELISPOT responses. In the liquid-ID group, WR052/F13L, a membrane glycoprotein, correlated with ADCC responses. CONCLUSIONS: MVA elicited antibodies to 15 vaccinia strain antigens representing virion membrane. Antibody responses to 2 proteins strongly increased and significantly correlated with increases in PRNT. Responses to these proteins are potential correlates of protection and may serve as immunogens for future vaccine development. CLINICAL TRIALS REGISTRATION: NCT00914732.