The Orthopoxvirus Vaccine: What It Is and Who Should Get It

An orthopoxvirus vaccine is any vaccine built to protect against the closely related viruses in the Orthopoxvirus genus, which includes smallpox (variola), mpox (monkeypox), cowpox, and vaccinia. Because these viruses share enough surface proteins that immunity to one confers partial or full protection against the others, a single vaccine platform can cover multiple threats. Two orthopoxvirus vaccines are currently available in the United States and much of the world: ACAM2000, a replicating vaccinia virus vaccine, and JYNNEOS (also called MVA-BN or Imvanex outside the U.S.), a non-replicating vaccine based on Modified Vaccinia Ankara. Who should get one depends on your occupation, your sexual health risk profile, and whether you have been recently exposed to someone with mpox.

Why One Vaccine Can Protect Against Multiple Viruses

The orthopoxviruses are so closely related genetically that your immune system has trouble telling them apart. Antibodies raised against vaccinia virus, the workhorse used in most orthopoxvirus vaccines, also bind to mpox virus proteins. A multicohort study found that both first-generation and third-generation smallpox vaccines produced antibodies that reacted with mpox virus, with the strongest responses targeting surface proteins called B5 and A33 and their mpox equivalents.¹ This cross-reactivity is the entire basis of orthopoxvirus vaccination: you do not need a separate vaccine for each virus in the family.

That cross-protection is real but imperfect. A population-based serological study in Taiwan looked at people who received historic smallpox vaccination before the program ended in the late 1970s. Among those vaccinated, the proportion who still had mpox-neutralizing antibodies decades later ranged from about 40% in the oldest birth cohorts to 76% in those vaccinated most recently before the program stopped.² The takeaway is that cross-neutralization is genuine but wanes over time and is partial rather than absolute. A person vaccinated against smallpox in 1975 has some residual protection against mpox, but probably not enough to count on fifty years later.

The Vaccines Available Today

Three orthopoxvirus vaccines see clinical use around the world, and they differ in important ways regarding who can safely receive them.

ACAM2000

ACAM2000 is the direct descendant of the original smallpox vaccine. It is a live, replication-competent vaccinia virus grown in cell culture, replacing the older Dryvax vaccine that was produced on calf skin.³ It is administered with a bifurcated needle that pricks the skin, producing a characteristic “take” lesion at the vaccination site.⁴ Because ACAM2000 is a live replicating virus, it can cause serious complications in people with weakened immune systems or certain skin conditions, and the virus can spread from the vaccination site to other people through close contact. This makes it powerful but not universally safe.

JYNNEOS (MVA-BN)

JYNNEOS is based on Modified Vaccinia Ankara, a strain of vaccinia virus that was repeatedly passed through chicken embryo cells until it lost the ability to replicate in human cells.⁵ The virus enters your cells and presents its proteins to your immune system, but it cannot produce new infectious virus particles. This makes JYNNEOS dramatically safer for immunocompromised individuals and people with skin conditions like eczema, where a replicating vaccine could cause a dangerous complication called eczema vaccinatum. JYNNEOS is given as a two-dose series, typically four weeks apart, by either subcutaneous injection or intradermal injection.

LC16m8

LC16m8 is a live attenuated vaccinia vaccine used primarily in Japan. It replicates to a limited degree but produces smaller skin lesions and fewer side effects than older vaccines. A recent randomized trial in people at high risk for mpox, including individuals with well-controlled HIV, found that LC16m8 was immunogenic and raised no significant safety concerns, though its clinical efficacy against mpox remains inconclusive.⁶ LC16m8 is not widely available outside Japan, so for most people the practical choice is between ACAM2000 and JYNNEOS.

Who Should Get Vaccinated

Recommendations differ depending on whether the goal is occupational protection, mpox outbreak response, or general preparedness. The two main sets of U.S. guidelines cover different populations and different vaccines.

Laboratory and Healthcare Workers

In 2015, the Advisory Committee on Immunization Practices (ACIP) recommended routine vaccination with ACAM2000 for laboratory personnel who directly handle cultures or animals infected with replication-competent vaccinia virus, recombinant vaccinia viruses, or other orthopoxviruses that infect humans, including mpox, cowpox, and variola. Healthcare workers who treat or anticipate treating patients with vaccinia infections can also be offered ACAM2000, though this recommendation carries a slightly lower strength.⁷ The CDC’s own assessment concluded that the benefits of vaccinating these workers are likely greater than the potential harms.⁸

People at Risk for Mpox

During the 2022 mpox outbreak and beyond, ACIP recommended JYNNEOS for adults aged 18 and older who are at risk for mpox during an outbreak, regardless of which clade of mpox virus is circulating.⁹ In practice, “at risk” during the 2022–2023 clade IIb outbreak primarily meant men who have sex with men and who have multiple sexual partners, people diagnosed with a sexually transmitted infection in the prior six months, people whose sexual partners fall into those categories, and sex workers. The risk groups for a clade Ib outbreak, such as the one that emerged in Central Africa, may differ and include broader community and household exposure.

Modeling work on clade Ib scenarios in England found that targeted vaccination of higher-risk groups is highly efficient, often driving the reproduction number below one even when less than half the population is vaccinated. A non-targeted approach, by comparison, would require vaccinating roughly two-thirds of individuals to achieve the same effect.¹⁰ This underscores why public health agencies focus vaccination campaigns on defined risk groups rather than pursuing mass vaccination.

How Well the Vaccines Work in Practice

The strongest real-world effectiveness data come from the 2022–2023 mpox outbreak. A multijurisdictional case-control study in the United States found that a single dose of JYNNEOS provided about 75% protection against mpox, and two doses raised that to roughly 86%.¹¹ That second dose matters. If you have only received one shot, you have meaningful protection but a substantially lower ceiling than the full series provides.

A newer vaccine platform using synthetic MVA showed that vaccinated volunteers developed antibodies that cross-reacted with mpox virus, with measurable neutralizing antibody responses across all dose groups after two doses.¹² These results, while from a small trial, reinforce the principle that MVA-based vaccines generate real cross-protection against mpox.

Post-Exposure Vaccination

Getting vaccinated after a known exposure to mpox is a separate question from pre-exposure vaccination, and the evidence here is more mixed. A systematic review and meta-analysis found that the overall post-exposure effectiveness of MVA-BN (JYNNEOS) was about 20%, a figure that did not reach statistical significance and had wide confidence intervals.¹³ That pooled figure, however, masks significant variation between studies. One contact-tracing study in Madrid during the 2022 outbreak found adjusted post-exposure vaccine effectiveness of about 89% among close contacts vaccinated within 14 days of exposure.¹⁴

The discrepancy likely reflects timing and study design differences. Post-exposure vaccination works best when given soon after the exposure and before symptoms appear. If you have been in close contact with someone who has mpox, public health officials will generally recommend getting vaccinated as soon as possible, ideally within four days and no later than 14 days after the last exposure. Even if the protection is less robust than what pre-exposure vaccination provides, it can reduce the chance of infection and may make any illness that does develop less severe.

Safety and Side Effects

The safety profiles of ACAM2000 and JYNNEOS are dramatically different, which is the main reason JYNNEOS is preferred for most civilians and all immunocompromised individuals.

ACAM2000 carries a known risk of myopericarditis, an inflammation of the heart muscle or its lining. A prospective safety study in U.S. military personnel found rates of myopericarditis around 3 to 6 per 1,000 vaccinees, though nearly all cases were subclinical, meaning they showed up on testing but did not cause symptoms. The adjusted odds ratio for myopericarditis after vaccination was 1.3, a modest and non-significant increase over the background rate.¹⁵ Still, this risk means ACAM2000 should not be given to people with known cardiac conditions, and all recipients need screening and monitoring.

JYNNEOS, by contrast, does not replicate in human cells and has a much milder side-effect profile. Injection-site soreness, redness, swelling, fatigue, and headache are common but typically resolve within days. In people with atopic dermatitis (eczema), a population that faces severe risk from replicating vaccines, JYNNEOS produced no cases of eczema vaccinatum and no clinically relevant skin reactions.¹⁶ A separate study confirmed that MVA vaccination in people with atopic dermatitis caused no serious adverse events, with most reactions being mild to moderate and self-resolving.¹⁷

For people who develop serious complications from replicating vaccines, vaccinia immune globulin (VIG) is available. The FDA has licensed two intravenous formulations for managing progressive vaccinia, eczema vaccinatum, severe generalized vaccinia, and certain other complications.¹⁸ VIG can also be used as prophylaxis for people who are exposed to smallpox or vaccinia but cannot receive the vaccine because of contraindications.

People Living With HIV and Other Immunocompromised Groups

Because mpox disproportionately affected communities where HIV prevalence is higher, the safety and immunogenicity of JYNNEOS in people living with HIV has received close attention. A study examining T-cell responses after JYNNEOS vaccination in HIV-positive individuals found that both intradermal and subcutaneous vaccination was safe and did not cause major side effects. Intradermal vaccination actually promoted stronger T-cell responses than subcutaneous dosing. However, individuals with CD4 T-cell counts at or below 500 cells per cubic millimeter needed at least a booster dose to mount efficient virus-specific responses, and the strength of that response correlated directly with their CD4 count.¹⁹

This means people with lower CD4 counts are not excluded from vaccination, but they may need additional doses and closer immunological monitoring. The non-replicating nature of JYNNEOS makes it the clear choice for this population; ACAM2000 is contraindicated in people with HIV or other immunocompromising conditions because the live replicating virus could cause uncontrolled infection.

How Long Does Protection Last

This is one of the less settled questions. A narrative review of the evidence found that while seroconversion after JYNNEOS is generally robust, circulating antibody levels often drop rapidly, especially in people who had no prior exposure to any orthopoxvirus and in immunocompromised individuals. Neutralizing antibody responses against mpox virus specifically tend to be lower than those against vaccinia virus, and researchers still have not nailed down which antibody level actually correlates with protection.²⁰

The more encouraging finding is that T-cell responses appear to be more durable than antibody responses. Even when antibody titers fade, memory T cells may continue to provide a measure of protection. This mirrors what is known from historical smallpox vaccination, where cellular immunity persisted for decades even after antibody levels became undetectable. Booster strategies are being studied, but there is no firm consensus yet on when or whether a booster should be given after the initial JYNNEOS two-dose series for ongoing risk.

Routes of Administration

During the 2022 outbreak, limited vaccine supply led the FDA to authorize intradermal administration of JYNNEOS as a dose-sparing strategy. Instead of a full subcutaneous dose, a smaller amount is injected into the skin, which allows roughly five times as many people to be vaccinated from the same number of vials. A cohort study in Washington, D.C. found that serologic responses varied by route: people who received a combination of one intradermal and one subcutaneous dose had significantly higher IgG antibody levels than those who received both doses intradermally.²¹ In the HIV-positive population, intradermal dosing promoted stronger T-cell polyfunctionality compared to subcutaneous delivery, as noted earlier. These findings suggest that route of administration is not just a logistical question but can influence the quality and magnitude of the immune response.

Global Supply and Equity

The mpox vaccines that exist work reasonably well. The problem is getting them to the people who need them, especially in low- and middle-income countries where manufacturing capacity is limited. Supply constraints have been documented as a major barrier, with both ACAM2000 and JYNNEOS production concentrated in a small number of facilities.²² During the 2022 outbreak, wealthy countries secured the bulk of available JYNNEOS doses while African nations, where mpox has circulated for decades, went largely without. The clade Ib outbreak in the Democratic Republic of the Congo in 2023–2024 made this inequity hard to ignore.

Dose-sparing intradermal administration helps stretch supply, but it does not solve the fundamental manufacturing bottleneck. Longer-term solutions likely require technology transfer, regional production partnerships, and the development of vaccines that are easier and cheaper to produce at scale.

Next-Generation Vaccine Candidates

The mRNA technology that proved its speed during the COVID-19 pandemic is being applied to orthopoxviruses. BioNTech has developed BNT166a, a quadrivalent mRNA vaccine encoding four mpox virus antigens: A35, B6, M1, and H3. A phase 1 dose-escalation trial in healthy adults is evaluating its safety and immunogenicity.²³ The rationale for mRNA vaccines is appealing: they can be manufactured quickly once the antigen sequences are known, they do not require handling live virus, and they can be updated if new clades emerge with meaningful antigenic changes. Whether mRNA platforms will match or exceed the real-world effectiveness of MVA-BN remains to be seen, and late-stage clinical data are still years away.

Telling Infection From Vaccination

As more people receive orthopoxvirus vaccines, public health officials face a practical challenge: when someone tests positive for orthopoxvirus antibodies, how do you know whether that reflects vaccination or actual infection? Standard antibody tests cannot easily make the distinction because the immune responses look similar. Newly validated serological tools are starting to solve this problem. One approach uses the ratio of antibodies against specific mpox virus proteins to their vaccinia virus counterparts. A validated multiplex assay found that the ratio of antibodies to MPXV A35R versus VACV A33R could distinguish infection from vaccination with 97% sensitivity and 96% specificity.²⁴

A separate assay development effort identified that combining an antibody targeting a region present in mpox but absent from the MVA vaccine (MPXV A27L) with a ratio of B6R to VACV B5 antibodies yielded the best discrimination between infection and vaccination, with about 89% sensitivity and 80% specificity.²⁵ These tools matter for surveillance, outbreak tracking, and understanding population-level immunity. Without them, you cannot tell whether rising antibody prevalence in a community means the vaccine campaign is working or a silent wave of infections is underway.

Stigma, Trust, and Vaccine Uptake

Because mpox spread primarily through sexual networks during the 2022 clade IIb outbreak, vaccination campaigns had to navigate significant stigma. In the UK, a qualitative study found that LGBTQ+ community members reported both anticipated and experienced stigma from public health messaging about mpox, but that this had limited impact on vaccine-seeking behavior. Researchers attributed this to proactive community mobilization, third-sector organizations, and trusted relationships with local sexual health clinics.²⁶ Recommendations for reducing stigma in future outbreaks include peer support initiatives, clear communication about when it is safe to return to normal activities, and co-designing public messaging with affected communities.²⁷

Stigma operates through indirect pathways as well. A study of African immigrants in the United States found that mpox stigma did not directly predict vaccine willingness, but it lowered vaccine confidence and increased vaccine hesitancy, which in turn reduced willingness.²⁸ In other words, stigma does not make people refuse the vaccine outright, but it erodes the trust that makes people willing to show up for it. For public health workers designing outreach, this means that destigmatizing mpox messaging is not a nicety but an operational requirement for getting doses into arms.