Orthopoxviruses are a genus of viruses that includes the variola virus, the mpox virus (formerly monkeypox), cowpox, and vaccinia virus. Smallpox was one of the most devastating infectious diseases in human history until a global vaccination campaign led to its eradication in 1980. Orthopoxvirus vaccines remain relevant due to the continued existence of lab stocks of variola virus and the emergence of zoonotic threats like mpox. The cessation of mass vaccination over forty years ago has led to a population with waning or no immunity, creating a vulnerability that drives the development of newer vaccines balancing strong protection with improved safety profiles.
The Global Need for Orthopoxvirus Vaccination
The need for orthopoxvirus vaccination has shifted dramatically from a mass public health campaign to a highly targeted strategy. The recurring threat posed by mpox, which has demonstrated the potential for significant international spread, is the main driver for current efforts. While the smallpox vaccine provides cross-protection against mpox due to the viruses’ shared antigens, the focus is now on proactive prevention in specific populations.
Current strategies emphasize pre-exposure prophylactic (PrEP) vaccination for individuals at sustained high risk of occupational or community exposure. This includes laboratory personnel who handle orthopoxviruses, specific healthcare workers, military personnel, and public health response teams. Targeted vaccination is also recommended for those in communities where mpox transmission is occurring.
The goal of this selective approach is to create a ring of immunity around potential exposure points. Post-exposure vaccination is also used, ideally administered within four days of exposure to a confirmed case to prevent infection or lessen disease severity. This targeted use contrasts sharply with the pre-1980 era, which saw widespread immunization aimed at eradicating a disease with a mortality rate as high as 30%.
Generations of Orthopoxvirus Vaccines
Orthopoxvirus vaccines are broadly classified into generations based on their composition and the degree of attenuation of the vaccinia virus strain used. The first generation of vaccines, such as Dryvax, utilized historical vaccinia strains that were unpurified and highly effective in eradicating smallpox. These vaccines are no longer mass-produced and were associated with significant side effects, leading to their discontinuation in the general population after smallpox eradication.
The second generation includes modern, purified, live, and replication-competent vaccines like ACAM2000. Derived from a clone of the first-generation virus, ACAM2000 actively reproduces in the vaccinated person. It is still stockpiled for use in emergencies or for high-risk personnel, but its use is limited due to safety concerns observed with earlier generations.
Third-generation vaccines represent a significant advancement, focusing on safety through further viral attenuation. The most prominent example is JYNNEOS (also known as Imvamune or Imvanex), which uses a Modified Vaccinia Ankara (MVA) virus. This vaccine is non-replicating; the virus can enter cells and stimulate an immune response but cannot complete its replication cycle within human cells. This characteristic makes it a safer alternative for specific populations.
How the Vaccines Differ in Administration and Safety
The fundamental difference between the second-generation ACAM2000 and the third-generation JYNNEOS lies in the virus’s ability to replicate, which dictates both the method of administration and the safety profile. ACAM2000 is a live, replicating virus administered percutaneously using a bifurcated needle to puncture the skin surface multiple times. This process causes a visible lesion, known as a “take,” which indicates successful vaccination and is a site from which the virus is shed.
ACAM2000 Safety Concerns
Because ACAM2000 is replication-competent, it carries the risk of severe side effects, including myocarditis and pericarditis (inflammations of the heart muscle). This vaccine also poses a risk of severe generalized vaccinia, progressive vaccinia, and accidental transmission to close contacts, particularly those who are immunocompromised. Consequently, ACAM2000 is contraindicated for people with conditions like eczema, those who are pregnant, and individuals with compromised immune systems.
JYNNEOS Administration and Safety
In contrast, JYNNEOS is a non-replicating virus, resulting in a far more favorable safety profile. It is administered as a two-dose series subcutaneously, similar to many other routine vaccinations, and does not cause the visible “take” lesion or viral shedding. The side effects are typically mild, primarily consisting of injection site reactions such as pain, redness, and swelling, as well as general symptoms like fatigue and headache.
The non-replicating nature of JYNNEOS means it can be safely given to people who are immunocompromised or have skin conditions like eczema, for whom ACAM2000 is unsafe. While JYNNEOS generally requires two doses for full effectiveness, its superior safety profile makes it the preferred choice for pre-exposure prophylaxis in most high-risk groups.