A comprehensive comparison of biological characteristics, efficacy, safety profiles and clinical guidance for the two main vaccines against monkeypox.
In our interconnected world, a virus that once smoldered in remote regions has now emerged on the global stage with surprising speed. Monkeypox, a relative of the dreaded smallpox, has leapt from geographical niches to worldwide concern, challenging our preparedness and pushing science to respond. As cases appear in communities worldwide, the race for protection has intensified, focusing attention on two vaccine candidates: JYNNEOS and ACAM2000.
These vaccines represent different generations of scientific advancement—one a refined modern formulation, the other a time-tested warrior with a proven track record.
Understanding how they compare—from their biological mechanisms to their safety profiles—is crucial not just for healthcare providers and policymakers, but for anyone concerned about emerging infectious threats. This article delves into the science behind these medical countermeasures, comparing their characteristics, effectiveness, and appropriate use in curbing the monkeypox threat.
To comprehend how JYNNEOS and ACAM2000 differ, we must first examine their fundamental biological characteristics and pharmacological properties. These differences form the foundation for their distinct safety profiles and administration requirements.
| Characteristic | JYNNEOS | ACAM2000 |
|---|---|---|
| Vaccine Type | Third-generation, non-replicating viral vector 4 | Second-generation, replication-competent live virus 4 |
| Platform | Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) 4 | Live vaccinia virus derived from Dryvax strain 4 |
| Replication Capability | Cannot replicate in human cells 4 | Replicates efficiently in human cells |
| Recommended Age | All ages (including children) 4 | 1 year and older (contraindicated in infants <12 months) 4 |
| Dosage & Schedule | Two 0.5mL doses, 28 days apart 2 5 | Single 0.0025mL dose 4 |
| Administration Route | Subcutaneous or intradermal injection 2 | Percutaneous scarification (15 jabs with bifurcated needle) 3 |
| Storage Requirements | Frozen (-25°C to -15°C); once thawed, stable at +2°C to +8°C for 4-8 weeks 5 | Frozen (-15°C to -25°C); after reconstitution, stable for 6-8 hours at room temperature or 30 days refrigerated 3 |
| Cost Per Complete Course | Approximately $115 4 | Approximately $139 4 |
Represents the more advanced third-generation vaccine technology, built on an attenuated vaccinia virus platform that has been modified to prevent replication in human cells.
The vaccine is produced using the "Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN), an attenuated, non-replicating orthopoxvirus" 4 .
A second-generation vaccine that contains a replication-competent vaccinia virus, closely related to first-generation smallpox vaccines that were instrumental in eradicating smallpox.
It is "a live vaccinia virus derived by plaque purification from a previously calf lymph-produced vaccine (Dryvax) and manufactured in Vero cells" 4 .
Despite their biological differences, both vaccines share a common strategic approach: they train the immune system to recognize and respond to orthopoxviruses, the family that includes smallpox, monkeypox, and vaccinia viruses.
As a non-replicating vaccine, JYNNEOS introduces two specific viral proteins to the immune system without producing infectious virus particles.
The "vaccine produces humoral and cellular immune responses to orthopoxviruses, generating neutralizing antibodies for the prevention of smallpox and monkeypox" 4 .
Because it doesn't replicate, it typically requires two doses to generate sufficient immune memory.
This vaccine uses a replicating vaccinia virus to create a localized infection that comprehensively engages the immune system.
The process involves administering the vaccine via scarification, where "the virus grows at the injection site, causing a localized infection or 'pock' to form" 6 .
This active infection site stimulates both antibody production and cellular immune responses, mimicking a natural infection without causing serious disease in most healthy individuals.
The immune response generated by these different approaches can be measured through neutralizing antibodies. Research comparing immunogenicity found that "the mean titer of neutralizing antibodies was 153.5" for JYNNEOS versus "79.3" for ACAM2000, suggesting a potentially stronger antibody response with the newer vaccine 4 .
When evaluating any medical intervention, the balance between benefits and potential harms becomes paramount. For monkeypox vaccines, this balance varies significantly between the two options.
| Parameter | JYNNEOS | ACAM2000 |
|---|---|---|
| Efficacy Against Monkeypox | 75% after one dose, 86% after two doses | Approximately 85% based on historical smallpox vaccine data 7 |
| Mean Neutralizing Antibody Titer | 153.5 4 | 79.3 4 |
| Common Side Effects | Pain, redness, swelling, itching at injection site; fever, fatigue, headache, muscle pain 4 5 | Pain, redness, swelling at vaccination site; fever, fatigue, headache, muscle pain, body aches 4 |
| Serious Risks | Rare severe allergic reactions 5 | Myopericarditis (5.7 per 1,000 vaccinees), encephalitis, progressive vaccinia, eczema vaccinatum, fetal death 3 |
| Special Population Considerations | Safe for immunocompromised, HIV+, pregnant people, and those with skin conditions 7 | Contraindicated in immunocompromised, HIV+, pregnant people, those with eczema or heart disease 3 4 |
| Virus Shedding & Transmission Risk | No risk of transmission 7 | Can be transmitted to close contacts until scab heals 3 |
The significant difference in safety profiles has made JYNNEOS the preferred vaccine for the current monkeypox outbreak. As noted by health authorities, "JYNNEOS is safe to use in all persons, including immunocompromised and HIV" positive individuals 7 .
This inclusive safety profile is particularly important since HIV-positive individuals represent a population at increased risk of monkeypox infection during the current outbreak.
ACAM2000 carries more substantial risks, including "myocarditis and/or pericarditis (suspect cases observed at a rate of 5.7 per 1000 primary vaccinees), encephalitis, progressive vaccinia, generalized vaccinia, severe vaccinial skin infections," and other serious complications 3 .
These risks are significantly elevated in certain populations, including those with cardiac disease, immune deficiency disorders, eczema, and during pregnancy 3 .
Another critical distinction lies in the potential for secondary transmission. With ACAM2000, "the live vaccinia virus can be transmitted to persons who have close contact with the vaccinee," requiring careful site care and precautions for approximately 30 days until the vaccination site fully heals 3 . JYNNEOS poses no such risk, as it cannot replicate or spread to others.
The gold standard for evaluating vaccine efficacy against monkeypox involves challenge studies in non-human primates, which closely mimic human disease progression and immune response. These controlled experiments provide critical evidence supporting vaccine authorization and use.
Groups of non-human primates (typically cynomolgus macaques) were selected for their similarity to human immune systems and susceptibility to monkeypox.
Animals received either JYNNEOS (two doses, 28 days apart), ACAM2000 (single dose), or placebo, following human vaccination schedules and routes.
After allowing time for immune development (typically 4-6 weeks post-final vaccination), all animals were exposed to a lethal dose of monkeypox virus via controlled injection or aerosol.
Researchers tracked survival rates, clinical symptoms, weight loss, viral loads in blood and tissues, and immune markers (antibodies and T-cell responses) daily for several weeks.
These experiments demonstrated that "pre-challenge vaccination with ACAM2000 resulted in a protective efficacy against death of 100% vs 0% survival in controls," with JYNNEOS showing identical perfect protection against lethal challenge 7 . The studies also revealed that "peak antibody levels [occur] 14-days after dose 2" for JYNNEOS, while "nAbs peak at day 28" for ACAM2000 7 .
The scientific importance of these findings cannot be overstated. They provided the foundational evidence that both vaccines generate sufficient cross-protective immunity against monkeypox to prevent severe disease and death, paving the way for their authorization during the 2022 global outbreak. The 100% efficacy in primate models under controlled conditions gave regulators confidence in their potential human effectiveness.
Advancing our understanding of orthopoxviruses and developing improved vaccines requires specialized tools and reagents. These materials enable scientists to study viral behavior, immune responses, and vaccine performance in laboratory settings.
| Reagent/Solution | Function in Research | Application Examples |
|---|---|---|
| Vero Cell Lines | Mammalian cell line used to propagate vaccinia and orthopoxviruses in laboratory settings | Vaccine production; viral replication studies 6 |
| Plaque Assay Reagents | Enable quantification of infectious virus particles through visible cell plaques | Measuring vaccine virus concentration; determining neutralization titers 6 |
| ELISA Kits | Detect and quantify specific antibodies against orthopoxvirus antigens | Evaluating vaccine immunogenicity; seroprevalence studies 9 |
| Plaque Reduction Neutralization Tests (PRNT) | Measure neutralizing antibody capacity in serum samples | Assessing functional immune response to vaccination 9 |
| Interferon-Deficient Mouse Models | Provide susceptible animal models for orthopoxvirus pathogenesis studies | Vaccine efficacy screening; challenge studies 9 |
| HEPES-Buffered Saline | Maintains pH stability during vaccine formulation and storage | Vaccine production and quality control 6 |
These specialized research tools have been instrumental in developing and evaluating both ACAM2000 and JYNNEOS. For instance, "ACAM2000 is derived from plaque purification cloning from Dryvax" using plaque assay methodologies 6 . Similarly, neutralization assays have been essential for comparing immune responses across vaccine platforms, demonstrating that "the mean titer of neutralizing antibodies was 153.5" for JYNNEOS versus "79.3" for ACAM2000 4 .
Understanding which vaccine to use in which circumstance has become increasingly important for healthcare providers and public health officials. Current recommendations reflect the different risk-benefit profiles of these two options.
For nearly all situations, JYNNEOS is the preferred vaccine due to its better safety profile and fewer contraindications.
As noted in clinical guidance, "JYNNEOS is preferred over ACAM2000 for monkeypox due to its safety profile" 7 .
The Centers for Disease Control and Prevention (CDC) recommends vaccination for specific at-risk populations, including:
The vaccine can be administered to those aged 18 years and older via the standard FDA-licensed regimen, while those younger than 18 can receive it under Emergency Use Authorization 5 .
ACAM2000 is reserved for circumstances where JYNNEOS is unavailable or contraindicated, and only when the potential benefits outweigh the risks for a given individual. Special consideration must be given to those with cardiac disease, immune deficiency, eczema, or pregnancy, where ACAM2000 is generally contraindicated 3 .
The emergence of monkeypox as a global health threat has tested our preparedness and response capabilities, while simultaneously showcasing scientific progress in vaccine development. JYNNEOS and ACAM2000 represent different generations of vaccine technology—both effective, but with distinctly different risk-benefit considerations.
Vaccination remains a cornerstone of our defense against emerging infectious diseases like monkeypox.
As the scientific community continues to gather real-world evidence, our understanding of these vaccines continues to evolve. While JYNNEOS has become the workhorse of the current outbreak response due to its superior safety profile, ACAM2000 remains available should supply constraints or special circumstances warrant its use. This two-pronged approach exemplifies the layered strategies needed to combat evolving public health threats in our interconnected world.
The story of these two vaccines continues to unfold as researchers study the durability of protection, the need for booster doses, and vaccine effectiveness against different monkeypox viral clades. This ongoing scientific inquiry ensures that our approach will continue to be refined based on evidence, offering the best possible protection against this reemergent threat.