30 May 2022 Episode 263 Monkeypox

Episode 263: Focus on Monkey pox

Dear colleagues,

After a relatively long break, I’m catching up and will focus on some papers related to Monkeypox, with many thanks to Patrick Smits.

INTRODUCTION

Ep 263-1: Branswell STAT May 25 discusses the various new or out-of-phase epidemics we witness, including the sudden Ad41-associated hepatitis and the unusual RSV season in children; the equally unusual Flu season and the emerging Monkeypox in adults. 

Is it all related to 2 years of “shielding” our immune system because of COVID? Has our immunity  been “weakened”, as many believe? Personally, I’m not so convinced, because we did not live in a sterile world anyway. 

Nevertheless, the unusual period had an influence on the developing immunity in young children, who were really less exposed to all kinds of micro-organisms at a critical age. 

But, much more importantly, in many parts of the world, vital childhood vaccination programs have been interrupted. That omission may have more far-reaching deleterious effects than Ad-41 or Monkeypox….

MONKEYPOX

Ep 263-2: WHO report of 19 May. Very nice and practical summary What I take from it:

• Lymphadenopathy is  a distinctive feature of monkeypox compared to other diseases that may initially appear similar (chickenpox, measles, smallpox).
• Tecovirimat has been approved by EMA.  See Ep 263-5 and 6
• Modified Vaccinia Ankara is a safer vaccine than the classical cowpox Dryvax  They may be applied post-exposure for several days. However, until now, the evidence is derived either from animal studies or at hoc info during epidemics.   See Ep 263-7, -8 and -9.   

Ep 263-3: Very didactic narrative review by Katlyn Jetelina:

• Monkeypox is on the rise for a while, especially the more virulent Central African strain with case fatality around 10 % 

• The present outbreak is with the less virulent West-African form (CFR 1-3 %).
• Present outbreak:
•  
•  
• During a 2003 outbreak in the U.S 26 % of cases were hospitalized and 15% had severe disease, but none died (Ep 263-9).  
• Zoonotic reservoir? 2003 outbreak:  American prairie dogs were infected by rodents and served as amplification vectors. American ground squirrels are also highly susceptible to the virus. If monkeypox were to become established in a wildlife reservoir outside Africa, the public health setback would be difficult to reverse.
• Bigger picture = more outbreaks

Ep 263-4: Kozlov in Nature Briefing 27 May  discusses 4 questions on Monkeypox

1. How did the current outbreak start? 

→ Can it all be linked to West-Africa or (less likely) is there a reservoir in the North?

2. Can a genetic change in the virus explain the last outbreak?

→ Presently unclear due to the large genome

3.   Can the outbreak be contained?

→  Possibility of ring vaccination, may even work post-exposure, due to long incubation time

→ Would be more difficult if there is already an animal reservoir in the North

4. Is the virus transmission pathway different from previous outbreaks?  

Hint of sexual transmission, but still possible that close contact is enough.

Ep 263-5: A: Hugh Adler Lancet Infect Dis 24 May 2022: Retrospective non-controlled study on management of monkeypox in humans.

Some observations:

• One family cluster
• All patients fully recovered
• PCR positivity in respiratory tract sometimes longer than in ulcerated lesions: crust formation is no guarantee that infectiousness is over
• Treatment with Brincidofovir in 3 patients was not successful and associated with elevated transaminases.
• Treatment with Tecovirimat in 1 patient apparently successful and no side effects 

Ep 263-6: Mucker in AAC 2013 activity of Tecovirimat against smallpox (variola) in cynomolgus macaques.

Mode of action: inhibition of p37, a highly conserved protein in all orthopox viruses (with no human homologue) that has a crucial role in formation of enveloped virions.  Viruses deficient in p37 are avirulent!

Post-exposure treatment is successful:  

Ep 263-7: Patricia Earl PNAS 2008 Rapid protection in a monkeypox cynomolgus macaque model by a single injection of a replication-deficient modified vaccinia virus Ankara strain (MVA), as compared to cowpox (Dryvax).

• From day 6 on after vaccination with MVA or Dryvax, the monkeys were clinically protected (except for 1 of 16 animals vaccinated with MVA), although viral loads and number of skin lesions were generally higher in the MVA vaccinated group.
• With only 4 days between immunization and intravenous challenge, however, MVA still protected whereas Dryvax failed.
• Protection correlated with the more rapid immune response to MVA compared to Dryvax, which may be related to the higher dose of MVA that can be tolerated safely.

Ep 263-8: Stittelaar J Virol 2005: a complicated study, showing that 2 doses of MVA provide equivalent protection against respiratory challenge with monkeypox in macaques as compared with either the classical smallpox vaccine (in casu Elstree) or a combination of MVA and Elstree.

 Ep 263-9: CDC Multistate outbreak of Monkeypox in 2003

30 persons have received smallpox vaccine since June 13:

• Pre-exposure to 7 persons and post-exposure to 23 persons with no serious adverse events.
• Among the 30 persons who received smallpox vaccine, three (10%) reported rash within 2 weeks of vaccination.
  • One of the three was confirmed as having monkeypox;
  • Another person had two skin lesion specimens that tested negative for orthopoxvirus and varicella zoster virus
  • No specimens were obtained for the third person.

Ep 263-10: UK Health Security Agency summarizes the evidence about MVA-BN (Imvanex), a third generation live modified vaccinia Ankara vaccine, manufactured by Bavarian Nordic. 

• With 2 doses, it was shown 100 % effective in cynomolgus macaques against a lethal challenge of aerosolised monkeypox.    
• Preclinical studies and phase I/II clinical trials of MVA-BN have suggested that 2 doses of vaccine are immunogenic generating antibody levels considered protective against smallpox, and by extrapolation, monkeypox as well.
• Post-exposure prophylaxis: in fact limited evidence that it can prevent or modify disease, but it may help.
• It is not contra-indicated in children, pregnancy, breastfeeding, immune deficiency:  MVA as a vector for other antigens has been used widely without safety concerns.

Recommendations:

1. Pre-exposure prophylaxis for HCW

2. Post-exposure prophylaxis and
3. Laboratory Workers:

single dose, best within 4 days, but up to 14 days.  Risk assessment in appendix 6

4. Underlying conditions: eczema, immune suppression: balance the risks

Ep 263-11: Bisanzio et al in medRxiv 29 May de-dramatizes the present outbreak.

Their modeling of a monkeypox outbreak in 50 million people in a high-income, European country.

Seeding an individual-based model with 3, 30, 300 primary cases,

• Without public health emergency interventions—this could lead to
  • a median of 18, 118, and 402 of additional secondary cases, respectively;
  • a median duration would be 23, 37, and 37 weeks, respectively.

• Contact tracing and isolation of symptomatic cases, or contact tracing, isolation of symptomatic cases and ring vaccination of the primary case contacts would substantially reduce the median size of outbreaks by 66.1—88.6% and median duration by 60.8–75.6%.

PROVISIONAL CONCLUSIONS

• The present Monkeypox epidemic is relatively large for the Northern hemisphere, but is not (yet?) dramatic.
• The clinical picture is rather characteristic, once you are aware. 
• The virus is (much) less transmissible than SARS-CoV-2, requires close contact, but transmission via respiratory or sexual  route may occur.
• Although formal phase 3 trials are lacking, we have a promising and safe vaccine: modified vaccinia Ankara, in addition to the traditional smallpox vaccine.  They may be useful for ring vaccination, even in post-exposure settings.
• Tecovirimat is a promising therapeutic agent.

All the above seems rather reassuring, BUT …a bad surprise is never excluded when you deal with a virus, because a nasty variant and/or an animal reservoir under the radar are always a possibility….

Best wishes,

Guido