Vaccine Effective Against Smallpox in Military: Pivotal Trial

By Marilynn Larkin

November 20, 2019

NEW YORK (Reuters Health) - The modified vaccinia Ankara (MVA) vaccine protected against variola infection among members of the U.S. Army, and did not raise safety concerns, the pivotal trial revealed.

The vaccine, JYNNEOS (TM), was developed by Bavarian Nordic (Kvistgard, Denmark) and approved by the U.S. Food and Drug Administration on September 24 for the prevention of smallpox and monkeypox in high-risk adults 18 and older.

"The study demonstrated that the peak neutralizing titers - believed to be the immune correlate against orthopox viruses - induced by MVA were non-inferior to ACAM2000," Bavarian Nordic CEO Paul Chaplin said in an email to Reuters Health.

ACAM2000, previously approved to prevent smallpox, is based on a replicating vaccinia virus, and can have toxic effects such as cutaneous reactions that may be severe in populations with immunodeficiencies or skin disorders.

By contrast, MVA does not replicate in cells and so is not associated with major cutaneous reactions.

"The trial also showed that the neutralizing titers induced by a single vaccination with MVA were comparable - i.e., also non-inferior - to those induced by ACAM2000 at a time (two weeks post-vaccination) when the vaccine is believed to have induced a protective response," he said.

For the phase 3 open-label study, Chaplin and colleagues randomly assigned 440 participants (mean age, 23.5; about 15% women; 60% white) to receive two doses of MVA, one each at weeks 0 and 4, followed by one dose of ACAM2000 at week 8 (the MVA group) or one dose of ACAM2000 at week 0 (the ACAM2000-only group).

The primary end points were (1) noninferiority of the MVA vaccine to ACAM2000 with respect to the peak serum neutralizing antibody titers; and (2) attenuation of the ACAM2000-associated major cutaneous reaction by previous MVA vaccination, measured according to the maximum lesion area and the derived area attenuation ratio.

As reported online November 14 in The New England Journal of Medicine, in the MVA group, 208 (94%) participants received two MVA vaccinations, and 196 (89%) also received the the ACAM2000 vaccine. In the ACAM2000-only group, 213 participants (97%) received the single dose of vaccine.

At peak visits, MVA vaccination induced a geometric mean titer of neutralizing antibodies of 153.5 at week 6, versus 79.3 at week 4 with ACAM2000 (ratio, 1.94).

Further, at day 14, the geometric mean titer of neutralizing antibodies induced by a single MVA vaccination was 16.2 - the same as that induced by ACAM2000 - and the percentages of participants with seroconversion were similar (90.8% and 91.8%, respectively).

The median lesion areas of the major cutaneous reaction were 0 mm2 in the MVA group versus 76.0 mm2 in the ACAM2000-only group, resulting in an area attenuation ratio of 97.9%. In addition, there were fewer grade 3 or higher adverse events after both MVA vaccination periods in the MVA group compared with the ACAM2000-only group (17 vs. 64 participants with adverse events of grade 3 or higher, respectively).

Chaplin said, "The medical community now has a vaccine that has been shown to be as efficacious as traditional smallpox vaccines, but is suitable for the general population, including people with weakened immune systems."

"Such a vaccine, designed for the prevention of both smallpox and monkeypox, offers the potential to revise national vaccination policies (for) vaccinating people thought to be at a higher risk of infection, such as military personnel, healthcare professionals, first-line responders or people traveling to endemic areas (for monkeypox infections)," he concluded.

Dr. Talia Swartz, Assistant Professor of Infectious Diseases at the Icahn School of Medicine at Mount Sinai in New York City, commented by email, "The timeline is important to consider. The MVA group that received MVA prior to ACAM2000 received two doses of MVA, one each on weeks 0 and 4, followed by ACAM2000 at week 8; the ACAM2000-only group received ACAM2000 at week 0."

"Additional studies would be necessary to determine whether MVA without ACAM2000 would result in long-term equivalent levels of neutralizing antibodies," she told Reuters Health. "The timeline of three injections is important as this requires patient adherence, and even under this study, there were...patients who did not receive all three doses."

"Given that MVA appears to be safer, it may be an option for those who have contraindications to the traditional ACAM2000 vaccine," she added. "It will likely continue to be most relevant to high-risk individuals, notably military personnel."

The study was funded in part by Bavarian Nordic. Dr. Chaplin and seven coauthors are employees.


N Engl J Med 2019.