2 April 2023 Episode 327 MPOX update

Episode 327: Update on MPOX

Dear colleagues,

Two apparently “alarming reports” on MPOX caught my attention this weekend:

Ep 327-2: a report from Loire region in France, where over 50 % of new cases occurred in vaccinated subjects

Ep 327-8 A: a message from CBS News, suggesting a high chance (> 35 %) of a pending MPOX resurgence in US  

Time to make an overview of

• The state of the epidemic in Europe (Par 1), suggesting that we are in a “calm phase”  
• Various (observational retrospective) studies in Europe and US (Par 2), suggesting a rather good overall effectiveness of 1 dose of MVA-BN vaccine
• A Dutch study on the immunogenicity of this vaccine in healthy volunteers (Par 3), showing rather moderate levels of neutralizing Ab induced
• The CDC modeling (Par 3), which is rather conditional and apparently mainly meant to encourage vaccination.   

Par 1 Status of European epidemic

Ep 327-1: ECDC report of 1 March 2023

Over 25,500 confirmed cases, presumably clade II = West-African (based on 489 genotypes performed)

98%  men and 96 % MSM (amongst 11,000 with known sexual orientation). One third HIV(+).

Symptoms see below

Only 783 (6%) hospitalized, of whom 271 required clinical care: 8 admitted to ICU and 6 died.

Only 5 cases by occupational exposure.

Only 38 new cases in Feb 2023.

Par 2 How effective is the MVA vaccine (one of two doses)

Ep 327-2: EWRS (Early Warning and Response System -ECDC French Team 1 April 2023:  New cases in France with evidence of vaccine failure Oct 2022-March 2023

Despite apparent absence of new French cases in the ECDC map: Between 1st January and 23rd march 2023, 18 new cases of mpox were diagnosed in France including 17 cases in the French region of Centre Val de Loire.

10/17 were correctly vaccinated: (presumably  only 1 dose = according to guidelines)

• 4 were HIV(+) and 9 on  
• All had rather mild disease, no hospitalization

All over France between Oct 2022 and Feb 2023: 40 new cases of whom 10 were correctly vaccinated.

Ep 327-3: Yanis Merad Euro Surveill: Retrospective study on post-exposure prophylaxis in Lyon France June-Aug 2022

11 out of 108 exposed subjects vaccinated with one dose of MVA-BN developed mpox: 10 % breakthrough infection

Potential risk factors : immune suppression and sexual exposure

Protection by previous smallpox vaccination = logical

Counter-intuitive: more protection if time since exposure > 5 days !!

Discussion:

1. Single dose not enough in subjects, especially in subjects with immune suppression and/or high (sexual exposure
2. Breakthrough in those who presented within 5 days for vaccination: may be because they realized that they had a large exposure?
3. Even if one dose is insufficient to protect against infection, it may protect against severe disease? But this could not be shown in the present study (all patients had relatively mild disease)

Ep 327-4 A: Marta Bertram Lancet Infect Dis March 2023 : Effectiveness of one dose of MVA-BN in gay and bisexual men (GBMSM) multisite in England July-Oct 2022

Method:

• Case-coverage: vaccine coverage among cases is compared with coverage in the eligible population,
• Estimated from doses given to GBMSM and the estimated size of at-risk GBMSM.

Calculated vaccine effectiveness

• 0-13 days after single dose = -4 % (CI -50 tà +29 %)
• > 14 days after single dose = 78 % (CI 71 to 85 %)

Ep 327-4 B:  Agunbiade Sex Transm Infect Jan 2023: single center study on clinical aspects in 15 patients with breakthrough mpox: no clinical difference between those who were unvaccinated and those with BTI after 1 dose.

Ep 327-5:  Yael Wolff Sagy Nature Med March 2023: Effectiveness of a single dose of MVA-BN in at risk males Israel  

Methods: retrospective cohort.  2000 “high risk males (either PLWH with other STI or taking PrEP for HIV) of whom about half received the single dose vaccine

Result: calculated 86 % effectiveness

Multivariate analysis showed protective effect of vaccination and living in Tel Aviv as a risk factor.

PDE5 inhibitor = phosphor-di-esterase 5 inhibitor for erectile dysfunction

Ep 327-6: Amanda Payne MMWR Dec 2022: Reduced risk for mpox after 1 or 2 doses MVA in US July-Oct 2022

Vaccine eligible =

• either MSM living with HIV acquired through male-to-male sexual contact,
• injection drug use, or both,
• or who are eligible for HIV preex­posure prophylaxis [HIV-PrEP]

Among JYNNEOS (= MVA-BN vaccine-eligible men aged 18–49 years in 43 U.S. jurisdictions,

MPOX incidence among unvaccinated persons was

• 9.6 times as high as that among persons who had received 2 vaccine doses and
• 7.4 times as high as that among persons who had received only the first dose

Simplified message:

Par 3 How much neutralizing Ab induced?

Ep 327-7: Luca Zaeck Nat Med Oct 2022: Low levels of monkeypox virus-neutralizing antibodies after MVA-BN vaccination in healthy individuals

1. MPXV-neutralizing antibodies can be detected after historic smallpox vaccination

(Endpoint titer = binding Ab in ELISA; PRNT50 : 50 % plaque reduction neutralization titer)

2. Also MPX neut after MPX infection (PCR-pos): not dependent on historic

3. However, a two-shot MVA-BN immunization series in non-primed individuals yields relatively low levels of MPXV-neutralizing antibodies.

Conclusion: Role of MPXV-neutralizing antibodies as a correlate of protection against disease and transmissibility = currently unclear

→ cohort studies following vaccinated individuals needed to assess vaccine efficacy in at-risk populations.

T cell immunity needs to be evaluated

Par 4: Resurgence of MPOX in US?

Ep 327-8 A: CBS News quotes CDC:

• Modelers predict a greater than 35 % chance of a resurgence of MPOX in the coming months
• While only 23 % of the “at risk” population has received any vaccine.

Ep 327-8 B: Actual CDC modeling

Data on coverage by jurisdiction can be found here: https://www.cdc.gov/poxvirus/mpox/cases-data/mpx-jynneos-vaccine-coverage.html

Clearly, this model is only valid IF

• mpox reintroduction occurs
• and no additional vaccination or sexual behavior adaptations occur.

Therefore, it is rather a strategy to encourage people at risk to take the vaccine asap ….

MY PRELIMINARY CONCLUSIONS

1. In the European epidemic, over 25,000 cases have been confirmed, almost exclusively in MSM, with 6 % hospitalizations, but very low numbers of ICU (8) and death (6).  Recent numbers are low
2. Because of the limited availability of the vaccine, only high risk subjects were vaccinated and mostly only with one dose. According to English, Israeli and US data, vaccine effectiveness has been high (in the range of 80 %), but it clearly increases with 2 doses (according to US data).  French data on limited number, seem less favorable.
3. Even after 2 doses of the vaccine in healthy people, induction of neutralizing antibodies seems rather low, but we have no idea of what level would be required for protection and no idea about the role of various parts of the immune system.  
4. The - at first view – “alarming” modeling of CDC is in fact rather a warning that the at risk US population is presently under-vaccinated if/when the epidemic recurs.

Clearly, more fundamental and epidemiological work is needed:

• Evaluate the various arms of the immune system after vaccination in healthy subjects, but also in PLWH  and with other forms of immune suppression.
• Identify antigens of MPOX, relevant to indice protection in animal models and design more adapted and safe vaccines
• Design prospective studies with the existing vaccines, in case of a resurgence of MPOX to identify correlates of protection.

Best wishes,

Guido