F1000Research 2022, 11:1519 Last updated: 14 DEC 2022

SYSTEMATIC REVIEW

Vaccine approach for human monkeypox over the years and

current recommendations to prevent the outbreak: a rapid
review [version 1; peer review: awaiting peer review]
Rifat Ara 1,2, Tajrin Rahman 2,3, Rima Nath2,3, A.M.Khairul Islam1,2,
Miah MD Akiful Haque2, Md. Ferdous Rahman1, Mohammad Hayatun Nabi3,
Mohammad Delwer Hossain Hawlader3
1International Centre For Diarrhoeal Disease Research, Dhaka, 1212, Bangladesh
2Public Health Professional Development Society (PPDS), Dhaka, 1215, Bangladesh
3Department of Public Health, North South University, Dhaka, 1229, Bangladesh

v1 First published: 14 Dec 2022, 11:1519 Open Peer Review

https://doi.org/10.12688/f1000research.127644.1
Latest published: 14 Dec 2022, 11:1519
https://doi.org/10.12688/f1000research.127644.1 Approval Status AWAITING PEER REVIEW

Any reports and responses or comments on the

Abstract article can be found at the end of the article.

Background: The World Health Organization has declared human
monkeypox as a global health emergency on 23 July 2022. This
indicates that the outbreak poses a serious risk to global health and
requires a united worldwide response to stop the virus from
spreading and possibly turning into a pandemic. Vaccines can play a
vital role in this context, contributing to pre- and post-exposure
prophylaxis.
Methods: The aim of our rapid review was to go through the
background of the vaccine approach for human monkeypox over the
years and to find out what current guidelines are highlighting relating
to it. A rapid review with a systematic search and manual searching
have been performed here.
Results: 22 relevant published articles from MEDLINE bibliographic
database and 8 vaccine recommendations from manual searching
have been deliberated here.
Conclusion: The significant synopsis of this review is that the
smallpox vaccine is the only immunization option for monkeypox so
far, and it is up to 85% effective to prevent the infection. Third-
generation smallpox vaccines are advised over first and second
generations due to their minimal side effects. Healthcare providers
and lab professionals at risk are on the priority list to get vaccinated,
as well as pregnant women or lactating mothers, and
immunocompromised or chronically ill patients can get vaccinated if
they are surely exposed to the monkeypox infection. Lastly,
JYNNEOS/IMVAMUNE is the current most preferable smallpox vaccine
that is highly advised for the latest outbreak of human monkeypox
but more clinical trials on humans should be conducted to evaluate its
safety, efficacy, and adverse events.

 
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Keywords
Monkeypox, Vaccine approach, Vaccine recommendations, Global
health emergency

This article is included in the Emerging Diseases

and Outbreaks gateway.

This article is included in the Trends and

Advances in Counteracting Mpox: A Global
Public Health Emergency collection.

Corresponding author: Rifat Ara (rifat.ara@icddrb.org)

Author roles: Ara R: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Software, Supervision, Validation,
Visualization, Writing – Original Draft Preparation; Rahman T: Conceptualization, Data Curation, Formal Analysis, Methodology,
Software, Validation, Writing – Original Draft Preparation; Nath R: Conceptualization, Data Curation, Formal Analysis, Methodology,
Software, Validation, Writing – Original Draft Preparation; Islam AMK: Conceptualization, Data Curation, Formal Analysis, Methodology,
Software, Validation, Writing – Original Draft Preparation; Haque MMA: Conceptualization, Data Curation, Formal Analysis,
Methodology, Software, Validation, Writing – Original Draft Preparation; Rahman MF: Data Curation, Formal Analysis, Methodology,
Software, Validation, Writing – Original Draft Preparation; Nabi MH: Conceptualization, Funding Acquisition, Investigation, Methodology,
Project Administration, Resources, Validation, Visualization, Writing – Review & Editing; Hawlader MDH: Conceptualization, Funding
Acquisition, Investigation, Methodology, Project Administration, Resources, Validation, Visualization, Writing – Review & Editing
Competing interests: No competing interests were disclosed.
Grant information: The author(s) declared that no grants were involved in supporting this work.
Copyright: © 2022 Ara R et al. This is an open access article distributed under the terms of the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite this article: Ara R, Rahman T, Nath R et al. Vaccine approach for human monkeypox over the years and current
recommendations to prevent the outbreak: a rapid review [version 1; peer review: awaiting peer review] F1000Research 2022, 11
:1519 https://doi.org/10.12688/f1000research.127644.1
First published: 14 Dec 2022, 11:1519 https://doi.org/10.12688/f1000research.127644.1

 
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Introduction
Orthopoxviruses belong to the Poxviridae, the family of
enclosed viruses with large linear, twofold DNA genomes
(0.130 kb genome)1. Multiple species of this group can cause
serious human illness. Variola virus is the major human
pathogen in the family Orthopoxvirus and the causal agent
of smallpox. Concerns have been expressed over the use
of the variola virus or a similar genetic pathogenic orthopox-
virus as a bioweapon2,3 despite the elimination of smallpox.
In addition, there is fear that the variola virus could be
discharged inadvertently, such as from unused viral stocks.
Variola virus was discovered cold-stored in a United States
research laboratory, lending validity to the second possibility4.
Orthopoxviruses, such as monkeypox virus, cowpox virus,
and strains of vaccinia virus, are emerging zoonoses in many
parts of the world5–7. These viruses cause significant diseases
in both people and livestock. In reality, both the frequency and
severity of human monkeypox virus epidemics have increased6,8,9.
Monkeypox (MPX) is an infectious zoonotic disease largely
concealed throughout the smallpox era. It was not recognized
as a human disease until the late stages of smallpox eradication
campaigns. MPX’s concealment might be linked to the
comparable clinical manifestations of monkeypox and
conventional smallpox, making it difficult to distinguish
between the two. How the natural monkeypox virus is sustained
in the wild is a significant outstanding question. Currently,
natural monkeypox is restricted to humid forest regions in
West and Central Africa10. Nevertheless, the disease inci-
dence in the Democratic Republic of Congo has increased since
20016,11. The 2017–18 outbreak of monkeypox in Nigeria
spurred the launch of a comprehensive surveillance strategy.
Therefore, it is necessary to continue developing and refining
orthopoxvirus countermeasures12.
Early vaccinations used to eliminate smallpox used live,
unattenuated vaccinia virus strains derived from calf lymph,
like Dryvax13. These vaccinations are no longer manufactured
and were replaced by ACAM200014, a cultured cell, live
vaccinia virus vaccine, and MVA (Modified Vaccinia Ankara),
a replication-deficient (in human tissues) vaccine. Both calf
lymph and cell culture vaccinations can cause severe adverse
reactions in humans, involving autoinoculation of an eye,
widespread vaccinia, eczema vaccinatum, recurrent vaccinia,
myocarditis, as well as death13,15,16. In the absence of a more
significant global threat posed by orthopoxvirus illness,
these safety issues make the broad usage of this vaccine
unethical. A substantial number of individuals are inappropriate
for ACAM2000 due to security concerns, particularly those
with immunological weaknesses and common skin disorders
such as dermatitis14. ACAM2000’s safety issues encouraged the
development of more extensively attenuated third-generation
vaccines, such as MVA and Lc16m817. The U.S. Food and
Drug Administration has recently approved JYNNEOS, the
Barvarian Nordic variant of the MVA vaccine, to prevent small-
pox. JYNNEOS protects animals from lethal orthopoxvirus
infection, including monkeypox virus disease of nonhuman
primates, rabbitpox virus infection of rabbits, and vaccinia
virus infection of mice18,19. According to statistics from Africa,
F1000Research 2022, 11:1519 Last updated: 14 DEC 2022
the smallpox vaccine is at least 85% effective at preventing
monkeypox20. Similar to ACAM2000, MVA lacks known
protective targets, and both infections express thousands of
genetic variants unlikely to assist in protection21.
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 23rd 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 health-
care 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.
Methods
To conduct this rapid review, we searched MEDLINE
bibliographic database and relevant websites of WHO, CDC,
UN, UK Health Agency Security, and GAVI, to identify
potential articles describing several vaccine strategies, vaccine
efficacy, and vaccine challenges to prevent the monkeypox
outbreaks. A simple search term “Monkeypox” AND “Vaccine”
was used to find all the pertinent write-ups, and all published
documents up to the date of 30 June 2022 were included.
Rayyan QCRI tool was used to screen the articles. Primarily
we retrieved a total of 291 articles, and duplicate articles
(n= 4) were excluded. Two reviewers scrutinized 115 out of
287 articles through independent dual screening of titles and
abstracts. Finally, 22 articles were selected after full-text
evaluation, and data extraction was considered. The PRISMA
flow diagram describes the detailed procedure of article
selection (Figure 1). In the case of selecting articles, the
availability of the information regarding different vaccine
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Figure 1. PRISMA flow diagram for article screening and selection.
approaches for monkeypox and their outcome were under
primary consideration. Vaccine complications and chal-
lenges were our secondary objective to include in our review.
This review included all relevant published documents,
regardless of study type or geographical distribution, such as
original articles, perspective papers, review papers, workshop
reports, editorial letters, or comments. Because a translator
was not available in the team, articles written in languages
other than English were excluded.
For data extraction, key points such as article types, publication
year, study design, countries where vaccines have been
experimented with, targeted population, name and types of
vaccines, their clinical outcome (e.g., efficacy, effectiveness),
and challenges for vaccine actualization were assembled and
recorded in a structured Excel format. Moreover, we also
followed the vaccine recommendations mentioned in the
selected articles. We also did manual searching along with the
F1000Research 2022, 11:1519 Last updated: 14 DEC 2022
literature review to find out current recommendations by
different international health organizations regarding the
monkeypox vaccine guidelines. We mainly focused on the
advice from the World Health Organization (WHO), Centers for
Disease Control and Prevention (CDC), United Nations, UK
Health Agency Security, Germany’s Standing Committee on
Vaccination (STIKO), Gavi, the Vaccine Alliance, and
Canada’s National Advisory Committee on Immunization
(NACI). Recent vaccine recommendations, guidelines,
indications, and contraindications were gathered to map out
the updated status of monkeypox vaccines. Extracted data
was reviewed by a third reviewer to minimize the chances of
missing data or biases.
Results and discussion
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
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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 households29,30.
After the 1980s outbreak of monkeypox in African territories,
a long break took place studying preventive measures for

Table 1. Summary of included primary articles.

Author Publication Article type/ study Region/ Vaccine name Clinical outcome of monkeypox vaccine
year design country

Arita I. et al.28 1985 Assessment of Tropical rain Smallpox vaccine A 13% case-fatality rate was found where
special surveillance forests of 17 out of 131 individuals died within three
and research West and weeks of the exposure. All of them were
Central Africa unvaccinated youngsters aging under seven
years. The secondary attack rate among
unvaccinated contacts was around 15% and
was the same between 1982 and 1983 and
1970 to 1981.

Jezek, Z. et al.29 1986 Cohort study Zaire in the Smallpox vaccine The standard smallpox vaccine was 85%
Democratic effective in preventing monkeypox disease.
Republic of The attack rate for monkeypox among the
the Congo 12,070 unvaccinated household contacts
along with smallpox infection rates ranged
from 37% to 88%. Statistical analysis of
vaccination history and closeness of contact
revealed that new cases of monkeypox were
much more likely to occur in unvaccinated
than in vaccinated contacts and in households
rather than in more-casual contacts.

Jezek Z. et al.30 1987 A computerized Zaire, Africa Smallpox vaccine The secondary attack rate among the close
Monte Carlo model contacts was 0.030. The attack rate was
strongly related to the residence and the
vaccination status of the close contacts. The
secondary attack rate (for the first generation)
among unvaccinated contacts who lived in the
same residence as an index case was as high
as 0.110. In contrast, the corresponding rate
among vaccinated contacts who lived outside
the affected household was almost 30 times
lower (0.004).

Fine P.E. et al.31 1988 Analysis of data on Zaire, Africa Smallpox vaccine The secondary attack rate was 0.110 for the
monkeypox in Zaire (Vaccinia) unvaccinated contacts in the same household
over the five years and 0.038 for the contacts outside the same
1980–1984 family. The equivalent rates for contacts
who had vaccinations were 0.017 and 0.004,
respectively. Therefore, among those contacts
with a history of vaccination—70% (1099 out
of 1573) received a high level of protection
from the vaccine.

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Author Publication Article type/ study Region/ Vaccine name Clinical outcome of monkeypox vaccine
year design country

Jezek Z. et al.60 1988 Active surveillance Zaire, Africa Smallpox vaccine There was a significant correlation between
investigation the secondary attack rates of monkeypox and
two factors: the exposed person’s residence
and vaccination history. It was discovered
that the attack rate among individuals who
had never had a vaccination (7.47%) was
substantially higher than that among those
who had previously received a vaccination
(0.96%). Unvaccinated contacts who shared
a home with a monkeypox patient had the
highest attack rate (9.3%), which was seven
times higher than the rate for similarly
situated vaccinated household members
(1.3%).

Jamieson D.J. 2004 Commentary USA Smallpox The first evidence of community-acquired
et al.32 vaccine (Vaccinia monkeypox in the United States was reported
immune by the CDC at the beginning of June 2003.
globulin) The CDC advised smallpox (vaccinia) vaccine
(85% effective against monkeypox) due to
the high death rate linked with monkeypox
on the African continent and the lack of
experience with monkeypox in the United
States. Minor risk of fetal complications from
smallpox immunization during pregnancy
exists, resulting in premature birth and 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.

Hammarlund 2005 Observational USA Smallpox vaccine This study identified five vaccinated subjects
E. et al.34 prospective study (Live virus who came in contact with monkeypox and
vaccine) three vaccinated subjects who showed
complete protection against the onset of
monkeypox-induced symptoms. Although
the sample size was too small to provide
specific statistical estimates, the general
conclusion is that approximately half of those
who received the vaccine (3 of 8) continue to
have long-lasting protective immunity against
monkeypox.

Fleischauer A.T. 2005 Public health USA Smallpox vaccine 94% of previously vaccinated, exposed HCWs
et al.36 investigation tested positive for anti-orthopoxvirus IgG
antibodies. No individuals appear to have had
a significant change in anti-orthopoxvirus
IgG levels suggestive of effects due to recent
booster exposure. So, smallpox vaccination
can provide protection for a long period
of time. It is also unclear whether recent
vaccination or infection produced a single
positive IgM result; the average duration of
IgM persistence after smallpox vaccination is
unknown. According to anecdotal evidence
with CDC vaccines, some primary vaccinees
may exhibit an IgM response for up to
6 months (unpublished data).

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Author Publication Article type/ study Region/ Vaccine name Clinical outcome of monkeypox vaccine
year design country

Nalca A. et al.61 2005 Review article USA Routine smallpox Clinical signs and symptoms of Monkeypox
vaccine were found to be more pronounced in
unvaccinated patients. Chills and/or sweats,
headache, backache, sore throat, cough,
shortness of breath, and lymphadenopathy
have been observed in 90% of unvaccinated
patients.

Huhn G.D. 2005 Retrospective USA Smallpox vaccine The significant finding of this study was
et al.33 analysis of clinical that previous smallpox vaccination was
reports and active not associated with disease severity or
and passive hospitalization. Seven patients (21%; median
surveillance age: 39 years, range: 33–47 years) reported
of suspected previous smallpox vaccination or had
Monkeypox cases recognized smallpox scars. Nevertheless,
bivariate and multivariate analyses found
no difference in illness severity or inpatient
hospitalization in patients with a reported
history of smallpox vaccination.

Cono J. et al.37 2006 Perspective review USA Smallpox vaccine According to the US FDA’s pregnancy
(Vaccinia) classifications of bioterrorism medical
countermeasures, the smallpox vaccine is
categorized as unlicensed or category C and
indicated for potential use during monkeypox
infection. The use of smallpox vaccination,
where they are available, for pregnant women
in an emergency situation when there is a
high chance of life-threatening exposure to
an infectious disease will likely be advised,
despite unknown dangers to the fetus.

Karem K.L. 2007 A follow-up, USA Smallpox vaccine In this study, 24% of the participants had
et al.35 household-based, previous smallpox immunization history
case control study during childhood. The results of this
study indicate that remote vaccination
against smallpox (30 years earlier) does
not completely protect against systemic
orthopoxvirus infection; in some cases, it may
prevent systemic disease, but the relative
contributions of infectious inoculum and
route of exposure, in addition to remote
vaccination, may significantly affect whether
systemic illness, asymptomatic infection or
atypical illness manifest.

Rimoin A.W. 2010 An active Democratic Smallpox vaccine The frequency of human monkeypox has
et al.6 population-based Republic of substantially increased by 20-fold in rural
surveillance Congo DRC 30 years after widespread smallpox
immunization campaigns stopped. They found
that the risk of human monkeypox is inversely
correlated with smallpox immunization. The
risk of monkeypox was 5.2 times lower in
those who received vaccinations than in those
who did not (0.78 vs. 4.05 per 10,000).

Kennedy J.S. 2011 Phase I/II USA LC16m8 (an The main objective of this trial was to compare
et al.38 randomized, attenuated cell the safety and immunogenicity of LC16m8
double-blind, culture–adapted with Dryvax in vaccinia-naive participants.
comparative clinical Lister vaccinia It has been found that, in order to prevent
trial smallpox human monkeypox, LC16m8 is a feasible next-
vaccine) generation vaccination alternative to first-
generation smallpox vaccines, at least in high-
risk groups. Its clinical efficacy against human
monkeypox has not yet been determined.

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Author Publication Article type/ study Region/ Vaccine name Clinical outcome of monkeypox vaccine
year design country

Rimoin, A.W. 2011 Short commentary Democratic Dryvax, Monkeypox risk was 5.21 times lower
et al.41 Republic of ACAM2000 (Live in vaccinated individuals compared to
Congo Vaccinia Vaccine) unvaccinated individuals, showing that >80%
protection was maintained for >30 years. With
an efficacy of 85% at the present incidence
rate, one Monkeypox infection may be
avoided for every 600 people who received
the vaccine in monkeypox-endemic areas.
The only smallpox vaccination that has been
shown to be effective in people is live vaccine
inoculation.

Kalthan E. 2018 Monkeypox Alindao- Smallpox vaccine In 87.5% of cases, the absence of smallpox
et al.62 outbreak Mingala vaccination was linked to severe presentations
investigation Study Health of Monkeypox. In this study, 19.2% of the
District of participants had a smallpox vaccination scar,
Central and the overall attack rate was lower in those
African who had received the vaccine (0.95/1000)
Republic compared to those who had not (3.6/1000).

Petersen, B.W. 2019 Prospective cohort Democratic IMVAMUNE Due to reporting so many adverse events of
et al.42 study Republic of (Third generation first- and second-generation smallpox vaccine,
Congo smallpox this study aims to follow up the cohort of
vaccine) health workers who have received two doses
of the third-generation smallpox vaccine.
Based on approaches, it was decided to study
the ability of vaccination with IMVAMUNE to
prevent monkeypox in DRC HCWs. The study
commenced in February 2017 and is currently
ongoing while study participants undergo
immunologic monitoring and follow-up for
exposure to monkeypox virus.

Harapan H. 2020 Online based cross- Indonesia IMVAMUNE® A clinical trial is ongoing to evaluate the
et al.43 sectional study Smallpox Vaccine safety and efficacy of a monkeypox vaccine
among HCWs. That is why the objective of
this study was to evaluate the acceptance
and willingness to pay (WTP) for the vaccine
among HCWs in Indonesia, where 96.0% of
the participants expressed acceptance of
free vaccination. The new generation of the
vaccine, IMVAMUNE, has been developed with
improved safety profiles, and a clinical trial
is ongoing to evaluate its safety and efficacy
in preventing monkeypox among HCWs
in the Democratic Republic of the Congo
(registered in ClinicalTrials.gov under identifier
NCT02977715).

Yong S.E.F. 2020 Case study Singapore Smallpox In May 2019, a traveler from Nigeria to
et al.44 vaccination Singapore was investigated as a confirmed
(ACAM2000; monkeypox case. 8 lower risk contacts and
Sanofi Pasteur 23 close contacts were found. Smallpox
Biologics Co) vaccination was made available to close
contacts as postexposure prophylaxis. Of the
22 close contacts, 14 chose to receive the
immunization, 2 had contraindications, and 6
contacts refused to get vaccinated. On days
6–8 of the review, a scab or ulcer was present
in every vaccine recipient. Slight fever and
minor swelling at the injection site were side
effects, but no serious adverse events were
reported.

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Author Publication Article type/ study Region/ Vaccine name Clinical outcome of monkeypox vaccine
year design country

Bankuru S.V. 2020 Compartmental Worldwide Smallpox vaccine To evaluate vaccination decision-making, a
et al.50 epidemiological game-theoretical approach was used. The
model, game theory model quantifies the smallpox vaccine’s costs
approach 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 disease is
preventable and can be eliminated through
vaccination in a semi-endemic equilibrium.
However, vaccination alone cannot wholly
eradicate monkeypox in an equilibrium where
it is entirely endemic.

Whitehouse 2021 Surveillance Democratic Smallpox vaccine The incidence among confirmed case
E. R. et al.63 Republic of patients was nearly three times greater (16.4
the Congo per 100 000) among those assumed to be
unvaccinated than those assumed to be
vaccinated (6.0 per 100 000). The incidence
among those who were assumed to have had
vaccinations was similar to that in the Bumba
zone between 1981 and 1985 (6.3 per 100
000). These results support earlier studies
that suggested a degree of cross-protection
against monkeypox might be conferred by
historical vaccination against smallpox.

Nguyen, P.Y. 2021 Review of retrieved Nigeria Smallpox vaccine Only 10.1% of Nigeria’s population had
et al.49 epidemiologic received the smallpox vaccine as of 2016,
and demographic and the serologic immunity level was
data from monthly 25.7% among those who had received the
and weekly vaccination compared to 2.6% in the general
epidemiologic population. Using the expected linear rate of
reports decline over time from vaccination, the cross-
immunity protection for monkeypox of 85% of
smallpox vaccination decreased to just 23.1%
among those who received it. Epidemiological
data suggest that having received a smallpox
vaccination in the past offers at least some
protection against serious monkeypox
infections. The total population immunity
level has significantly decreased during
the previous 45 years due to population
expansion in the postvaccination era. So, the
role of vaccination in preventing monkeypox
is being considered, and clinical trials for
healthcare workers have been suggested
here.
**Table legends: USA= United States of America, CDC= Centers for Disease Control and Prevention, HCWs= Health care workers, FDA= Food and Drug
Administration, DRC= Democratic Republic of the Congo, WTP= Willingness to pay

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
studies33–35. 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.

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are the two articles that put forward the opinion regarding
smallpox vaccination during pregnancy31,36. 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 tri-
als 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.
F1000Research 2022, 11:1519 Last updated: 14 DEC 2022
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 MVA45,46, 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-expo-
sure 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 individu-
als exposed to the monkeypox virus regardless of concurrent
illnesses, pregnancy, breastfeeding, or poor immune system52.
On the other hand, the CDC also advised ACAM2000 immu-
nization 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
JYNNEOS52,53. 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,
Page 10 of 15

Table 2. Most recent vaccine recommendations by different organizations.
Article
Vaccines and immunization for
monkeypox: Interim guidance
Smallpox/Monkeypox Vaccine
(JYNNEOS™): What You Need
to Know
Monkeypox and Smallpox
Vaccine Guidance
Considerations for Monkeypox
Vaccination
Five things you need to know
about monkeypox
F1000Research 2022, 11:1519 Last updated: 14 DEC 2022
Recommended by Time and Vaccine Recommendations
Date
World Health 14 June Mass vaccination for monkeypox is not required. It is advised
Organization (WHO) 2022 to administer a suitable second- or third-generation vaccine to
contacts of patients as post-exposure prophylaxis, ideally within
four days of the initial exposure. Pre-exposure prophylaxis
is advised for healthcare workers at risk, lab employees who
handle orthopoxviruses, and clinical laboratory staff who do
monkeypox diagnostic tests. A robust information campaign, a
solid pharmacovigilance program, and joint vaccine effectiveness
studies with standardized methodologies and data gathering
technologies are all required to support vaccination programs.
Smallpox or monkeypox vaccination decisions should be based on
a thorough analysis of risks and benefits on a case-by-case basis.
Centers for Disease 01 June JYNNEOS™ vaccine is approved by the Food and Drug
Control and 2022 Administration (FDA) to prevent monkeypox disease in adults
Prevention (CDC) 18 years or older at high risk for monkeypox infection. CDC
recommends JYNNEOS™ for certain laboratory workers, clinic
teams who care for patients infected with orthopoxvirus, and
emergency response team members who might be exposed to
the viruses. JYNNEOS™ is usually two doses, four weeks apart.
People who have received other types of smallpox vaccine in the
past might need one dose only. Booster doses are recommended
every two or 10 years if a person remains at continued risk for
exposure to orthopoxviruses. It has been recommended to
receive JYNNEOS™ due to exposure to the monkeypox virus
regardless of concurrent illnesses, pregnancy, breastfeeding, or
weakened immune system.
Centers for Disease 02 June In conjunction with the Advisory Committee on Immunization
Control and 2022 Practices (ACIP), the CDC provided recommendations on who
Prevention (CDC) should receive smallpox vaccination (JYNNEOS/ ACAM2000) in a
non-emergency setting. At the time, ACAM2000 immunization
was advised for military personnel and lab workers who handled
specific orthopoxviruses. ACAM2000 vaccination has the potential
for more side effects and adverse events than the newer vaccine,
JYNNEOS. Thus, on November 3, 2021, ACIP recommended
JYNNEOS pre-exposure prophylaxis as an alternative to ACAM2000
for some people at risk of orthopoxviruses. In order to prevent
monkeypox infection, the CDC advises that the vaccination be
administered within four days of the date of exposure. A vaccine
administered between four and 14 days after exposure may not
prevent the disease, but it may lessen the symptoms. People
exposed to the monkeypox virus and who have not had the
smallpox vaccine within the last three years should think about
receiving it.
Centers for Disease 30 June Currently, JYNNEOS (also known as IMVAMUNE or IMVANEX)
Control and 2022 and ACAM2000, two vaccines approved by the U.S. Food and
Prevention (CDC) Drug Administration (FDA), are accessible to prevent monkeypox
infection. There is currently no information on these vaccinations’
effectiveness in the ongoing outbreak. ACAM2000 vaccination
should not be administered to those with certain medical issues,
such as weakened immune system (e.g., HIV), cardiac disease,
eye disease treated with topical steroids, congenital or acquired
immune deficiency disorders, atopic dermatitis/eczema, infants,
or pregnancy. The Advisory Committee on Immunization Practices
(ACIP) decided on November 3, 2021, to suggest JYNNEOS pre-
exposure prophylaxis as a substitute for ACAM2000 for some
people who may be exposed to orthopoxviruses.
Gavi, The Vaccine 17 May The smallpox vaccine was vital to eradicating smallpox decades
Alliance (GAVI) 2022 ago, and this vaccine can be highly effective – 85% – in preventing
monkeypox. However, first-generation smallpox vaccines are no
longer offered to the general population. For the protection of
smallpox and monkeypox, a more recent vaccination based on
vaccinia was licensed in 2019; however, it is also not yet widely
accessible.
Page 11 of 15
 F1000Research 2022, 11:1519 Last updated: 14 DEC 2022

Article Recommended by Time and Vaccine Recommendations

Date

Monkeypox: Vaccine
recommended for Canadians
at high risk of exposure
National Advisory 10 June Health Canada has authorized IMVAMUNE; a vaccine often used
Committee on 2022 to treat smallpox and monkeypox. Anyone who has come into
Immunization (NACI)- touch with a case or has been in an environment with a high
Canada chance of exposure is given one dosage. Additionally, a second
dose was advised to be given under specific conditions only.
Immunocompromised individuals, pregnant or nursing women,
as well as children and young people, may be administered
vaccinations if their risk of exposure is higher. Given the scope
of the outbreaks so far, mass vaccination campaigns against
monkeypox among the populace are not currently required due
to the size of the outbreaks.

HHS Announces Enhanced
Strategy to Vaccinate and
Protect At-Risk Individuals
from the Current Monkeypox
Outbreak
The U.S. Department 28 June In an effort to stop the spread of monkeypox, the U.S.
of Health and Human 2022 Department of Health and Human Services (HHS) unveiled an
Services (HHS) improved national vaccination program. The plan will vaccinate
and safeguard persons susceptible to monkeypox, prioritize
vaccine distribution in areas with the greatest caseloads, and
offer direction to state, territorial, tribal, and municipal health
officials to help with their preparation and response operations.
A four-tier distribution plan for the JYNNEOS vaccine will be used,
giving priority to regions with the most significant prevalence of
monkeypox cases. The number of people at risk for monkeypox
who also have pre-existing illnesses, such as HIV, will determine
how many doses of JYNNEOS are distributed within each tier.
In order to guarantee that the communities with the greatest
need have access to immunizations to prevent monkeypox, HHS
will continue to develop and strengthen its vaccine supply and
distribution strategy.

Monkeypox: German panel
recommends vaccine for risk
groups
Germany’s Standing 09 June The vaccine advisory body advised IMVANEX smallpox vaccine
Committee on 2022 from Bavarian Nordic. The panel also recommended that because
Vaccination (STIKO) vaccine supplies are limited, those who have recently been
exposed to the monkeypox virus should be the first to receive
it. According to STIKO, the recommended vaccination course
with IMVANEX entails two doses given at least 28 days apart to
individuals who have never received a smallpox vaccination and
one dose for those who have.

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 monkeypox55–57.
Conclusion
As the rapidly spreading monkeypox outbreak in 2022
represents a global health emergency, the WHO labeled it
as a “public health emergency of international concern
(PHEIC)” and asked for an international response to
collaborate on sharing vaccines and treatments59. So,
governments worldwide should come forward immediately
to impose preventive measures, including screening, isolation,
and vaccine prophylaxis where necessary.
The limitation of our review was that we only searched
the MEDLINE database due to the target of rapid review
within a short period of time. A systematic review can also
be performed in this regard, especially on vaccine clinical
trials. Despite having some deficiencies, this rapid review
on vaccine approach and recommendations concluded with
several significant points, including:
• The smallpox vaccine has been the only immunization
option for human monkeypox till now. There is no
specific vaccine manufactured only for monkeypox yet.
• The smallpox vaccine is up to 85% effective in
preventing monkeypox infection and it can provide
protection for a very long period.
• There are three categories of smallpox vaccine. The
first-generation vaccine is not available in the market
anymore. The third-generation vaccine is recommended
over the first and second generation due to fewer side
effects and adverse events.
• Smallpox vaccine is recommended for all monkeypox
virus exposed individuals regardless of pregnancy,
chronic illnesses, or poor immunological conditions.
• JYNNEOS/IMVAMUNE is the latest third-generation
smallpox vaccine that almost all international health
organizations have mostly recommended. A human
clinical trial of this vaccine is currently ongoing,

Page 12 of 15

and the results could offer information which would be
very much helpful to evaluate the safety and efficacy
of the vaccine. More trial studies should be conducted
in the future to find out the accuracy.
• The vaccine is highly recommended as pre-exposure
prophylaxis to all healthcare workers at risk and con-
tact as post-exposure prophylaxis, but mass vaccination
is not required until now.
•  dditionally, human monkeypox is preventable and
A Reporting guidelines
can be eradicated through vaccination alone in a
semi-endemic equilibrium but not in a fully endemic
equilibrium.
Ethical considerations
The approval for this rapid review has been granted by the
Ethics Review Committee of North South University,
Bangladesh on 2nd July 2022. Reference number: 2022/OR-NSU/
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