Mpox Update

There is good news and bad news. I’m a glass half-full kind of guy, so let’s start with the good news.

But, first, a situation update from the World Health Organization (WHO) though this includes data only up through 9/22/24 (Multi-country outbreak of mpox, External situation report #38 – 28 September 2024 (who.int)). A large outbreak of Mpox has been taking place in 15 African countries, particularly in the Democratic Republic of Congo (DRC), Burundi, and Nigeria with more than 30,000 suspected cases so far just for 2024, but it is likely the number is far higher.

There are two clades (strains) of Monkeypox virus contributing to the current outbreak – clade IIb (newly recognized at that time) that previously spread globally to at least 123 countries beginning in May of 2022 and was declared a Public Health Emergency of International Concern (PHEIC) at that time, but was brought under relative control a year later, at which time the PHEIC was terminated. While clade IIa, the ancestor clade had a mortality rate in African outbreaks on the order of 1 percent, the case fatality rate for clade IIb globally was fortunately only about 0.2 percent. Whether the virus evolution to a more transmissible clade IIb involved a trade-off in virulence, or whether the reduction in mortality was related to better access and better health care systems outside of Africa, or both, is not currently known.

Clade IIb has been noted to be primarily affecting and spread by men who have sex with men. For reasons that are not totally understood, this year has seen an uptick in clade IIb cases again. Then, earlier this year, a new clade Ib emerged, which has spread outside of the DRC to neighboring countries that had not previously had Mpox cases, and it is believed that, in part, to have occurred through heterosexual sex workers. However, clade Ib has disproportionately affected young children (not seen with clade IIb) and has caused high morbidity and mortality in children, raising concern transmission may also be occurring through direct contact with infected animals and through close contact with infected adults. While the case fatality rate for clade Ia, the ancestor to this new clade, ranged between 4 and 10 percent, the case fatality rate for suspected cases this year (a mix of clade Ib and IIb, but probably dominated by the large increase in Ib) is almost 2.7 percent.

The Mpox outbreak continues to grow in each African country that has detected cases. Guinea just reported its first case after Gabon had recently reported its first case. Clade II cases have been detected in all six WHO regions of the world. The U.S. has reported 113 cases in 2024 through August. Fortunately, confirmed cases of clade 1b have only been reported in three countries outside of Africa thus far, all in travelers to Africa, except for the most recent case who is reported to have only traveled to the UAE.

On to the good news. First, yesterday, the WHO approved the first diagnostic test for the monkeypox virus for emergency use (https://news.un.org/en/story/2024/10/1155351).  The newly approved test is the Alinity m MPXV assay and this is a real-time PCR (polymerase chain reaction) test that enables detection of monkeypox virus DNA from human skin lesion swabs.  The test is made by Abbott Molecular, a U.S. company. While this is a tremendous advancement in our ability to diagnose MPox cases, this test will still require being performed in clinical laboratories with trained laboratory technicians (as opposed to point-of-care testing that can be done at home or in a doctor’s office).

Prompt diagnosis is important in isolating infected patients and minimizing further spread to those in close contact with the infected patient.

The second piece of good news is that vaccines have arrived in Africa (finally!) and immunizations began today in the DRC in the North Kivu province, beginning with high-risk persons (including health care workers, first responders, and close contacts of infected persons). On September 13, WHO announced the MVA-BN (Modified vaccinia Ankara – Bavarian Nordic) vaccine as the first vaccine against mpox to be added to its prequalification list https://www.who.int/news/item/13-09-2024-who-prequalifies-the-first-vaccine-against-mpox.

MVA-BN is a highly attenuated virus vaccine utilizing the Chorioallantois Vaccinia virus Ankara poxvirus, which was previously created as a safer alternative smallpox vaccine, that is also effective against the monkeypox virus. Unlike the original smallpox vaccine, this modified virus is incapable of replication and therefore does not produce disease in the recipients, nor does it pose a risk of transmission to those in close contact of vaccinees. The vaccination schedule includes two doses administered a month apart. The WHO reports that the MVA-BN vaccine given before exposure has an estimated 76% effectiveness in protecting people against mpox, with the 2-dose schedule achieving an estimated 82% effectiveness.

On the bad news front, a report on a recent outbreak of Mpox in Australia (New South Wales) since June of 2024 included 433 cases, of whom 26 required hospitalization. The concerning news is that 14 percent of those infected had previously received one dose of vaccine, and 40 percent of cases had been fully vaccinated with two doses.

Two days ago, a research letter was published in JAMA Network reporting the decline in antibody responses following MVA-BN vaccination https://jamanetwork.com/journals/jama/fullarticle/2824688. (Keep in mind that antibody levels always decrease following vaccination or acute infection. The real concern is whether immunological memory is long-lived so that antibodies can be quickly produced recalled and produced in response to infection or reinfection.) The authors cited research demonstrating that two doses of MVA-BN vaccine provided 66% effectiveness and 1 dose provided 36% effectiveness at peak immunity during the 2022 mpox outbreak, which clearly demonstrates that the vaccine is immunogenic and provides the population of those vaccinated with some degree of protection. Thus, the concern is not one of immunogenicity, but rather the longevity of protection and whether further booster doses may be necessary. Of note, the current recommendation in the U.S. is only for the initial two-shot series in those at risk for Mpox.

High levels of neutralizing antibodies were seen after infection, but not after vaccination. However, it is difficult to know the clinical significance of this because the correlates of immune protection are not known for Mpox, and not all infections require neutralizing antibodies for prevention of infection. Even if neutralizing antibodies are required, we don’t know what level of antibodies are required.

Thus, it is a bit difficult to know whether the findings of this study are of concern in and of themselves, however, coupled with the report above out of Australia, as well as a report of a cluster of MPox infections in persons previously vaccinated do suggest that boosters in high-risk individuals may be necessary within a year of the initial series. If public health officials determine this to be the case, it will pose a challenge in Africa given that vaccine is in short supply and there is not enough to vaccinate all those in the countries involved in the current outbreak even with just the first dose of the initial series.

We clearly need more research on MPox vaccines, and given a study suggesting that our only antiviral against the monkeypox, TPOXX (tecovirimat) did not appear effective in accelerating recovery in clade Ib cases (though it did not rule out that it might be effective in preventing more severe disease if given earlier and to higher risk individuals) https://www.biospace.com/drug-development/mid-stage-study-finds-only-mpox-drug-ineffective-against-current-outbreak#:~:text=SIGA%20Technologies%20%E2%80%99%20antiviral%20drug%20TPOXX%20%28tecovirimat%29%20is,topline%20readout%20of%20the%20Phase%20II%20PALM007%20trial, we also need more research into effective antivirals.