Originally published by our sister publication Infectious Disease Special Edition

By Marie Rosenthal, MS

Immunogenicity after mpox vaccination lasted longer among people who had received a smallpox vaccination as a child than among those who had not, according to data reported at the ESCMID Global 2024 Congress, held in Barcelona, Spain (oral abstract 0212). 

However, Marc Conrad Shamier, MD, a PhD candidate at the Erasmus Medical Center, in Rotterdam, the Netherlands, was quick to point out that it is unknown what this means for the risk for infection.

In May 2022, an mpox outbreak caused by the clade IIb strain of the virus provided the first epidemiological evidence of community mpox transmission outside of historically affected countries, according to the CDC. The modified vaccinia Ankara-Bavarian Nordic (MVA-BN, sold as Jynneos, Imvamune and Imvanex) vaccine was made available to at-risk populations to contain the global outbreak. 

“The mpox virus is closely related to the variola virus, the causative agent of smallpox and closely related to the vaccinia virus, which was given originally in the smallpox vaccine,” explained Dr. Shamier, who presented one-year immunogenicity data after receipt of the MVA-BN vaccine during the outbreak. However, it was unclear how much the old smallpox vaccination, which was given to young children until smallpox was eradicated, would protect against mpox. Countries stopped giving smallpox vaccine in the 1970s.

So, the researchers looked at the immunogenicity of people born before and after 1974, when the Netherlands stopped giving smallpox vaccine to its residents, to see whether it had any effect on MVA-BN vaccination given today.

The researchers looked at two cohorts. The first cohort included men who have sex with men as well as laboratory workers who worked with pox viruses in BSL3 settings. They were followed periodically from January 2022 to December 2023 with a planned one-year final follow-up. 

“The second cohort consisted of men visiting sexual health clinics where  routinely collected serum samples of GBMSM who do STI checkups every 3 months, so for this cohort there was no specific ‘one-year final follow-up’. We analysed biobanked sera that were collected between Jan. 22 and Dec. 23,” Dr. Shamier explained.

They wanted to study the trajectories of the antibodies over the long-term after vaccination. 

Out of 118 MVA-BN vaccine recipients, 36 came back for the final follow-up visit. 

At first, they looked at the vaccine-specific immunoglobulin G geometric mean titers (VACV IgG GMT) based on an in-house enzyme-linked immunosorbent assay for vaccinia virus. The VACV IgG GMT levels were undetectable among 14 of 21 people who had not received smallpox vaccination, but only in one person who had received a childhood smallpox vaccine. 

People who were born before 1974 were presumed to have received a childhood smallpox vaccination and saw a “clear boost” in antibody titers, which were maintained after one year, even if they only received one dose of mpox vaccine, he explained. 

“In contrast if we look at people who did not receive childhood smallpox vaccinations—in the Netherlands, these are people born after 1974—we see that one month after the second dose, we see that everybody develops antibodies, but one year later, approximately 60% of participants lose detectable antibodies,” he explained.

The same results were seen in both cohorts. “Over time, we also see clear decrease in antibody titers [in those born after 1974],” he said.

Among the second cohort, six participants with polymerase chain reaction–confirmed mpox infections received mpox vaccinations, and they also saw “the antibodies nicely maintained at a stable level,” similar to those who had received smallpox vaccination as a child.

Next, they measured neutralizing antibody, which showed similar trends, according to Dr. Shamier. “We see people without preexisting immunity one year later have a strong decrease with very, very limited neutralizing antibody activity.”

On the other hand, “those vaccinated in childhood where we see neutralizing capacity is much better maintained,” he said.

The antibodies in individuals with preexisting immunity, whether from previous smallpox vaccination or infection, are long-lived, while antibodies in individuals without preexisting immunity are short-lived. 

“Infection induced antibodies appear to be more durable than those induced by MVA-BN vaccination,” he said. “And finally when we look at neutralizing antibodies, we see that the neutralizing capacity shows similar decay that’s most pronounced in those that did not receive childhood smallpox vaccination.”

Although the 2022-2023 mpox outbreak has abated, there are still sporadic cases occurring throughout the world, so it was important to continue to study ways to control mpox. 

Vaccination will continue to play “an important role in limiting the size of future outbreaks,” but it is also important to recognize, diagnose and treat cases early, Dr. Shamier said. Based on a recent study, they used mathematical modelling (2022 Euro Surveill 2024;29[17]:pii=2300532).

Unfortunately, he added it is not possible to know what these data mean for infection risk. 

“I’m only showing you immunogenicity data. These data say nothing about vaccine effectiveness,” he said. His study was not designed to find the antibody threshold that would indicate long-term protection against disease, Dr. Shamier explained.  

Dose-Sparing Regimen

In related news from the meeting, a dose-sparing intradermal mpox vaccination, which was used in the United States and other countries to ensure the vaccine supply, was found to be safe and generated an antibody response equivalent to that induced by the standard regimen at six weeks (two weeks after the second dose), according to findings from another study presented at the meeting (poster 3816).

The results suggest that antibody responses contributed to the effectiveness of dose-sparing mpox vaccine regimens used during the 2022 U.S. outbreak (MMWR Morb Mortal Wkly Rep 2023;72[20]:553-558).

In the United States, the National Institutes of Health’s National Institute of Allergy and Infectious Diseases sponsored a study of dose-sparing strategies to extend the limited vaccine supply.

The mid-stage study enrolled 225 adults aged 18 to 50 years in the United States who had not previously been vaccinated against mpox or smallpox. Participants were randomized to receive either the standard FDA-approved MVA-BN regimen, a regimen containing one-fifth of the standard dose or one with one-tenth of the standard dose. The standard dose was injected subcutaneously, while the dose-sparing regimens were injected intradermally. Participants in all study arms received two injections 28 days apart and were monitored for safety and immune response.

Two weeks after the second dose (study day 43), participants who received one-fifth of the standard dose had antibody levels equivalent to those of participants receiving the standard MVA-BN regimen, based on predefined criteria. By day 57, participants who received one-fifth of the standard dose had lower antibody levels than those in the standard regimen arm; the clinical significance of this difference is unknown. Participants who received one-tenth of the standard dose had inferior antibody levels at all measurements. The most reported adverse events were mild, local injection site reactions. Adverse events were similar across all arms of the trial, and no serious adverse events related to the vaccine were reported.

The researchers noted that because there are no defined correlates of protection against mpox, these findings cannot predict the efficacy of dose-sparing regimens with certainty.