Vaccine approach for human monkeypox over the years and current recommendations to prevent the outbreak: a rapid review

Current outbreak of monkeypox

Few occurrences of monkeypox outbreaks in humans have been reported outside of the African continent since the 2003 outbreak in 11 states of the USA²². After that a minor uptick was observed in 2017 but the outbreak of 2022 illustrates a distinct situation that may have been predicted because there were early indicators²³. 3413 cases with laboratory confirmation and one death have been reported to WHO from 50 countries in five WHO Regions between January 1, 2022 and June 22, 2022. 86% of cases with test confirmation were reported from the WHO European Region²⁴. As of 23^rd July 2022, WHO has issued the strongest call to action it is able to in relation to the global monkeypox outbreak by declaring it as a public health emergency of international significance²⁵. By this time, 20,675 confirmed cases of monkeypox and four deaths were reported from 29 EU/EEA countries, as of 25 October 2022²⁶.

Objective of this review

Several vaccine approaches have been applied over the years to prevent the spread of monkeypox infections. A vaccine has recently been approved for monkeypox; however, it is not yet widely available²⁷. Some countries may have smallpox vaccination products on hand that might be used if national guidelines are followed. Depending on the country, any request for vaccination items may be offered in limited numbers through federal authorities. Governments may want to explore immunizing close contacts as a post-exposure prophylactic measure or immunizing select groups of healthcare personnel as a preventative measure. Considering the recent clustered outbreak of monkeypox in several countries and declaring it as a global public health emergency, this rapid review aims to explore different vaccine approaches and plan over the years, challenges and current recommendations to prevent the outbreak.

Vaccine approach for human monkeypox over the years

A total of 22 articles have been found that analyzed and described the monkeypox preventive approaches through vaccination (Table 1). Over the years, researchers have explored active and passive surveillance, cohorts, public health investigations, and epidemiological data on monkeypox outbreaks and smallpox vaccination to see the efficacy and effectiveness of different generation vaccines against monkeypox infection. As a result, articles published from 1985 to date were included in our review. Our review perceived that all the articles talked about routine smallpox vaccines of different generations, and no specific vaccine has been manufactured for the monkeypox virus until now.

There are five articles published in 1980s that mainly investigated individuals of the African region who were routinely vaccinated against smallpox during their childhood and later exposed to the monkeypox virus. Among these five articles, Arita I. et al. assessed the special surveillance of tropical rain forests of West and Central Africa between 1970 to 1981 and 1982 to 1983, where a 13% case-fatality rate was achieved, and all of them happened to unvaccinated youngsters. Moreover, the secondary attack rate in unvaccinated contacts was around 15%²⁸. The other four articles analyzed data on the monkeypox outbreak in Zaire of the Democratic Republic of Congo (DRC) over five years (1980–1984). They concluded that the standard routine smallpox vaccine was 85% effective in preventing monkeypox²⁹, and the secondary attack rates were 0.110 in unvaccinated contacts living in the same households^29,30.

After the 1980s outbreak of monkeypox in African territories, a long break took place studying preventive measures for monkeypox until the outbreak emerged in the USA in 2003. The first indication of community-acquired monkeypox in the United States was reported by the Centers for Disease Control and Prevention (CDC) at the beginning of June 2003, and CDC advised the vaccinia smallpox vaccine be used as it was established to be 85% effective against monkeypox³². Seven articles have discussed the effectiveness of past smallpox vaccination among US citizens to prevent monkeypox, where almost all the studies found positive outcomes of vaccination except one. A retrospective analysis of clinical reports and active and passive surveillance of suspected monkeypox cases was done in 2005, where bivariate and multivariate analysis found no association of disease severity or hospitalization with previous smallpox vaccination³³. Vaccinated subjects showed good protection and less pronounced clinical signs or symptoms against the onset of monkeypox-induced disease in the rest of the studies^33–35. Another significant public health investigation was done in 2005, where 94% of the monkeypox-exposed healthcare workers tested positive for anti-orthopoxvirus IgG antibodies as they had a previous history of smallpox vaccination³⁶. Jamieson D.J. et al. and Cono J. et al. are the two articles that put forward the opinion regarding smallpox vaccination during pregnancy^31,36. According to them, the smallpox vaccine is considered category C (the human fetal risk of the drug as unknown due to no human studies or positive results in animal studies) approved by the US Food and Drug Administration (FDA), and minor risk to the fetus from vaccinia smallpox immunization during pregnancy exists that may result in premature birth, fetal and neonatal death. Nevertheless, given the potentially fatal risk of monkeypox infection, exposed women were urged to get the smallpox vaccine regardless of whether they were pregnant.

Another significant finding of our review was that despite having multiple animal trials of the vaccine directly against monkeypox, there is no sufficient evidence of clinical trials on humans yet. In recent times, a phase I/II randomized, double-blind, comparative clinical trial of LC16m8 (an attenuated cell culture–adapted Lister vaccinia smallpox vaccine) has been conducted on humans to compare the safety and immunogenicity of LC16m8 with the Dryvax vaccine³⁸. This trial showed that LC16m8 is a feasible next-generation vaccination alternative to first-generation smallpox vaccines to prevent human monkeypox, at least in high-risk groups. Although, its clinical efficacy against human monkeypox has not yet been determined. A clinical trial of a new generation IMVAMUNE® smallpox vaccine is ongoing to evaluate its safety and efficacy in preventing monkeypox among healthcare workers (HCWs) in the Democratic Republic of the Congo³⁹.

Right now, the Strategic National Stockpile (SNS) has three smallpox vaccines, among which ACAM2000® and JYNNEOSTM (also known as IMVAMUNE or IMVANEX) are the only two licensed smallpox vaccines in the United States⁴⁰. It has been found that the only smallpox vaccination effective in the people of the DRC was the live vaccine inoculation (Dryvax and ACAM2000)⁴¹. Monkeypox risk was 5.21 times lower in vaccinated individuals compared to unvaccinated individuals, showing that more than 80% protection was maintained for over 30 years⁴¹. A prospective cohort study was performed in 2019 to follow up the health workers of the DRC who have received two doses of the third-generation smallpox vaccine (IMVAMUNE) due to reporting so many adverse events of first- and second-generation smallpox vaccine⁴². Third-generation smallpox vaccine was better than the first- and second-generation. Though a clinical trial is ongoing to evaluate the safety and efficacy of the IMVAMUNE vaccine against human monkeypox among healthcare workers, an online based cross-sectional study was conducted among Indonesian health workers to evaluate the acceptance and willingness to pay (WTP) for the vaccine, where 96% of the participants expressed the acceptance of free vaccination⁴³. A case study in Singapore revealed that 64% of close contacts recovered rapidly from signs and symptoms of monkeypox due to accepting the ACAM2000 vaccine (Sanofi Pasteur Biologics Co) immediately after contact tracing⁴⁴.

The rate is inferior if we look into the recent smallpox vaccination status. In order to prevent smallpox from reemerging, WHO kept a stockpile of 200 million doses in 1980. However, when smallpox did not resurface in the late 1980s, 99% of the stockpile was destroyed⁴⁵. By 2019, the United States had received 269 million doses of ACAM2000 and 28 million doses of MVA^45,46, but by the time the 2022 monkeypox outbreak began, only 100 million doses of ACAM2000 and 65,000 doses of MVA remained in the stockpile⁴⁸. One of our included articles showed that only 10.1% of Nigeria's population had received the smallpox vaccine as of 2016, and the serologic immunity level was 25.7% among those who had received the vaccination compared to 2.6% in the general population⁴⁹. However, worldwide vaccination data is not known yet. Finally, there is one article that criticized the cost-benefit of mass vaccination. Bankuru S.V. et al. describe a compartmental epidemiological model and game theory approach that evaluated vaccination decision-making of a community⁵⁰. The model quantifies the smallpox vaccine's costs and advantages. This study determined that the ideal vaccination rate is approximately 0.04, meaning people should get vaccinated once every 25 years. Additionally, they discovered that monkeypox is preventable and can be eliminated through vaccination in a semi-endemic equilibrium (an infection that spreads only part of the year in a specific area). However, vaccination alone cannot wholly eradicate monkeypox in an equilibrium where it is entirely endemic⁵⁰.

What is the latest vaccine recommendation for human monkeypox?

After manual searching for vaccine recommendations, several guidelines were put in place suggested by different international health organizations (Table 2). According to WHO, mass vaccination for monkeypox is not required so far. They also advise administering a suitable second or third-generation smallpox vaccine to contacts as post-exposure prophylaxis (ideally within four days of initial exposure) and healthcare workers at risk as pre-exposure prophylaxis⁵¹. CDC recommends JYNNEOS™ for certain laboratory workers and clinic teams who are susceptible to virus exposure. JYNNEOS™ is usually issued in two doses, given four weeks apart. People who have received other types of smallpox vaccine in the past might be considered for one dose only. Booster doses are recommended every 2 or 10 years if a person remains at continued risk for exposure to orthopoxviruses. JYNNEOS™ is recommended for individuals exposed to the monkeypox virus regardless of concurrent illnesses, pregnancy, breastfeeding, or poor immune system⁵². On the other hand, the CDC also advised ACAM2000 immunization for military personnel and lab workers only, but it is not suggested for any immunocompromised health condition (such as diabetes or pregnancy) as ACAM2000 has the potential for more side effects and adverse events than JYNNEOS^52,53. The Vaccine Alliance-GAVI has recommended the vaccinia smallpox vaccine over the first generation and suggested increasing the availability worldwide due to the monkeypox outbreak⁵⁵. Other national health organizations, such as the National Advisory Committee on Immunization (NACI)-Canada, the U.S. Department of Health and Human Services (HHS), and Germany's Standing Committee on Vaccination (STIKO), have also suggested the latest smallpox vaccine (JYNNEOS/IMVAMUNE/IMVANEX) to fight against the recent outbreak of human monkeypox^55–57.

Ethical considerations

The approval for this rapid review has been granted by the Ethics Review Committee of North South University, Bangladesh on 2^nd July 2022. Reference number: 2022/OR-NSU/IRB/1001. This study did not directly involve any human participant; therefore, consent was not required.