25 Sept 2022 Episode 288 Monkeypox update and wrap-up?

Dear colleagues,

The MPX epidemic in the North seems to subside.  Time for some conclusions on clinical, epidemiological, surveillance, treatment and vaccination.

Par 1 Clinic and epidemiology

The epidemic in Belgium, neighboring countries and the North is coming down (left).  Contemporary official figures in Central Africa are very low (right), but presumably underreported.

Ep 288-1: Comprehensive report of ECDC on EU/EEA

Ep 288-2: WHO Global trends

Monkeypox reporting completeness

As of 22 Sep 20221

Total Confirmed Cases

Total Detailed Confirmed Cases2

% Detailed Cases reported

Region of the Americas

36,089

31,542

87.4%

European Region

24,256

24,106

99.4%

African Region

588

173

29.4%

Western Pacific Region

173

24

13.9%

Eastern Mediterranean Region

53

40

75.5%

South-East Asia Region

21

9

42.9%

1 Total confirmed cases shown as of date of last detailed case report for the WHO Region of the Americas and WHO European Region.

2 Note that in rare cases total detailed cases may exceed total confirmed cases due to ongoing data cleaning issues

Ep 288-3: Sciensano report for Belgium in Dutch (A) and French (B).

Until 20 Sept 757 cases in Belgium:

• 99 % men
• 92 % sexually transmitted
• 96 % skin lesions, 2/3 also ano-genital
• 56 % constitutional symptoms (fever, malaise…)
• 6 % hospitalized
• 1 death (underlying medical conditions)

Ep 288-4: Pittman medRxiv 29 May 2022: Clinical and Lab characteristics of hospitalized MPX in DRC

Prospective Observational study in Kole in 216 PCR confirmed cases between 2007-2011:

• Most common complaints: rash (96.8%), malaise (85.2%), sore throat (78.2%), lymphadenopathy (57.4%).
• Lesion distribution: centrifugal (face >hands and feet > arms and legs> trunk).  Apparently NOT ano-genital.
• Three deaths and 4/5 fetal deaths in infected pregnant women

Evolution of rash over time : max after 1 week, clearly diminishing after 2 weeks

Distribution of enlarged lymph nodes: mainly submandibular + cervica; less supraclavicular, axillar, inguinal

Constitutional and organ signs: malaise; headache, cough, anorexia and HEENT =Visual changes, Eye pain/discharge, Ear pain, Nasal discharge/congestion, Dysphagia, Sore throat, Conjunctive and other eye lesion, Nasal discharge/congestion/ rhinorrhea/nasal lesion, Mouth/throat lesions)

Association of various constitutional symptoms with lesion count and PCR

Routine lab: trend to liver- and kidney dysfunction in most serious cases

Co-infections were frequent:  

• Chickenpox, malaria, microfilariasis, giardiasis, ankylostomiasis, strongyloidiasis, filariasis, and hookworm.
• Other skin infections were often present, including infected wounds.
• Several complications were noted such as caseation of the eye, keratitis, etc.

The case fatality rate 1.4% (3/216) is much lower than previous studies: WHO in eighties 9.8 % and in nineties 3.7 %

But confirmation of frequent fatal fetal outcome (3/4).

Ep 288-5:  Kozlov Nature 22 Sept comments on relatively low death rate (22/59,000).

Death rate may be higher if children, old people, immunocompromised… are affected.  See two cases of immunocompromised subjects in Spain, who died from encephalitis.

Most hospitalizations for pain management, but some people hospitalized for “difficulties with breathing or brain swelling”.

CONCLUSION:

• The clinical picture and epidemiology of the present “Northern” MPX epidemic is clearly different from the endemic MPX in Central Africa. In fact the Northern epidemic is largely an STD in promiscuous gay men.
• The severity of the disease is dependent on the presence of co-infections and underlying immune deficiency.  Nevertheless MPX can be very serious also in immunocompetent individuals, requiring hospitalization, mainly for pain management.
• The case fatality is lower than originally presumed. In fact, a lower CFR is also seen in the most recent studies from Central Africa.  This could be a MPX strain effect, but it is also possible that only the most severe Central African cases were hospitalized in the past.

Par 2 Surveillance in wastewater: has been reported from several sites in Europe and US

Ep 288-6: La Rosa medRxiv 19 Aug: 3 samples positive out of 20 between 30 May and 1 Aug at Rome airport.

Ep 288-7: Wurtzer medRxiv 18 Aug P:  Detection and quantification of the MPX in sewersheds in Paris correlated temporally with the spread of the disease within the population.

Ep 288-8: Marlene Wolfe medRxiv 9 Sept: 9 selected sites in California between June 19 and August 1,

• MPXV DNA was detected at all nine sites
• 5 of 9 sites detected MPXV DNA prior to or within a day of the first case identified in the source sewershed.
• At 4 sites with >10 positive detections, a positive, statistically significant correlation (p <0.001) between MPXV DNA in wastewater solids and incidence rate of reported cases.

Ep 288-9: Giron-Guzman medRxiv 19 Sept: extensive testing of 24 wastewater plants in various areas in Spain

“ based on the wastewater data, the reported clinical cases seem to be underestimated and asymptomatic infections may be more frequent than expected.”

CONCLUSION: 

As with SARS-CoV-2, PCR analysis of wastewater can be an early warning system for emerging MPX epidemic.

Par 3 Tecovirimat as treatment for MPX?

Ep 288-10: Adam Sherwat NEJM 18 Aug reminds us that Tecovirimat was developed for smallpox, but for obvious reasons could not be tested in humans.  Instead it was shown to be active against MPX in primates and rabbitpox in rabbits.  The dose for human use was deduced from the monkey efficacy studies and from safety and pharmacokinetics in healthy volunteers. 

The present approval by CDC for “compassionate use (see below) thus is based on the “animal Rule”.   A potential problem is that the circulating MPX today belongs to a different clade than the one that usually circulates in RDC.

Par 3.1. Animal data

Ep 288-11: Jordan AAC May 2009: ST-246 (Tecoviromat) Antiviral Efficacy in a Nonhuman Primate Monkeypox Model

• Using iv infection with 5 X 107 PFU of the Zaire 79 strain of MPX (isolated from fatally infected person) in Cynomolgus macaques
• Tecoviromat 3, 10, 30 to 100 mg/kg for 14 days: start 3 days after infection = secondary viremia, but before lesions  appear

Result for 100 mg/kg: effect on lesions (left) and DNA viral load in blood (right) 

Result of 3 mg/kg

Summary results:

Conclusion:  Based on these results and comparison of pharmacokineticsz between macaques and humans: suggest that administration of an oral dosage of 400 mg once daily for 14 days will be effective for the prevention or treatment of smallpox or monkeypox infections in humans.

Ep 288-12: Grosenbach NEJM July 2018: Oral Tecovirimat for the Treatment of Smallpox

The minimum dose of tecovirimat required in order to achieve more than 90% survival in the monkeypox model in non-human primates was 10 mg per kilogram of body weight for 14 days,

Treatment should be started at the latest day 5 after infection for maximal effect.

Translation to humans in phase 1:

A dose of 600 mg twice daily for 14 days was selected for testing in humans and provided exposures in excess of those in nonhuman primates. No pattern of troubling adverse events was observed.

Par 3.2. Human data

Ep 288-13:  Festius Mbrenga medRxiv 28 Aug present an observational study on Tecoviromat in 14 patients of the Central African Republic.   

There is no control group and 11 patients were co-infected with malaria, of whom one was also HIV (+). 

One patient died after discharge in apparently good condition. His death considered unrelated to MPX or to Tecovirimat.

Most patients presented late 5-45 (median 21) days and a large proportion had respiratory distress that even (temporarily) increased during hospitalization

The main result, according to the authors:

• The rate of appearance of active lesions gradually decreased throughout treatment, with the median time to no new lesions being 5 days following the start of treatment.  
• Another outcome: 4 (31%) patients recovered without sequelae and 9 (69%) recovered with sequelae.

It is really unclear what all this means in terms of effects of Tecovirimat….

Ep 288-14: Kevin O’Laughlin MMWR 16 Sept report on good tolerability and safety of Tecovirimat in 549 MPX patients in the US.  

With regard to efficacy: it is not known whether the outcomes described for patients who received tecovirimat differ from those of patients who do not receive tecovirimat because no control group was included.

Ep 288-15:   CDC Expanded Access 15 Sept:

• For most patients with intact immune systems, supportive care and pain control may be enough.
• Tecovirimat should be considered for those with weakened immune systems.

Rationale:  because prognosis depends on multiple factors, such as initial health status, concurrent illnesses, previous vaccination history, and comorbidities, supportive care and pain control may not be enough for some patients

Reasons for limitation od indications:

• Lack of effectiveness data in humans.
• Unclear which patients might benefit most.
• Concern about development of resistance.

Some possible indications:

• Severe disease —such as hemorrhagic disease; large number of lesions such that they are confluent; sepsis; encephalitis; ocular or periorbital infections; or other conditions requiring hospitalization
• Involvement of anatomic areas which might result in serious sequelae that include scarring or strictures:
  • lesions directly involving the pharynx causing dysphagia, inability to control secretions, or need for parenteral feeding;
  • penile foreskin, vulva, vagina, urethra, or rectum with the potential for causing strictures or requiring catheterization;
  • lesions interfering with bowel movements (for example, severe pain);
  • severe infections (including secondary bacterial skin infections), especially those that require surgical intervention such as debridement

Ep 288-16: Nice review in Viruses Aug 22 by Almadhi on the development and patent literature of Tecovirimat.

CONCLUSION

• There is no in vivo proof that Tecovirimat is effective against the MPX strain that is currently causing the epidemic, but it is very likely (in view of the broad spectrum of the compound against Orthopoxviruses).
• Safety and pharmacology have been established in humans, but a major concern is the timing  od the treatment: it should start within the first five days after infection for maximal effect.

Par 4 Vaccination

Modified vaccinia virus 24 Ankara (MVA-BN, also known as Imvamune, Jynneos, or Imvanex) is a 3rd generation smallpox vaccine that was generated by serial passaging of the more pathogenic parental vaccinia virus (VACV), and is authorized as a vaccine against MPX in humans in a two-shot regimen.

However: no data on efficacy against MPX or even on neutralizing antibodies

Here 2 preprints on neutralization induction in healthy individuals

Par 4.1. Animal data

Ep 288-17: Stittelaar J Virol 2005  compared the MVA-BN vaccine with classical vaccinia as a preventive vaccine in a lethal respiratory MPX challenge in cynomolgus macaques and showed it to be highly efficacious and safe.

Ep 288-18: Patricia Earl PNAS 20   shows that the response a single vaccination with MVA intramuscularly is more rapid than with the Dryvax  (= vaccinia) by scratch in macaques, challenged intravenous with MPX Zaire 79. 

• Challenge at 6 or more days after vaccination with MVA or Dryvax, the monkeys were clinically protected (except for 1 of 16 animals vaccinated with MVA).
• With only 4 days between immunization and challenge, MVA still protected whereas Dryvax failed.

Reason: rapid immune response to MVA compared to Dryvax, related to the higher dose of MVA tolerated safely.

Par 4.2. Human data

Ep 288-19: Zaeck medRxiv 1 sept 22: Low levels of monkeypox virus neutralizing antibodies after MVA-BN vaccination in healthy individuals.

Figure 1. VACV (vaccinia virus)-reactive and MPXV-neutralizing antibodies after historic smallpox vaccination (= born before 1974) and MPXV infection (PCR-positive).

• Subjects who were vaccinated with vaccinia (born before 1974) have high antibody titers against vaccinia (left) and most have low neutralizing titers against MPX

• MPX infected subjects (PCR pos) have higher  neutralizing titers against MPX, irrespective whether vaccinated with vaccina (born before 1974) or not. 

Figure 2. VACV-reactive and MPXV-neutralizing antibodies after Imvanex (MVA-BN) vaccination

• Limited increase of antibodies against vaccina after 2nd  MVA-BN vaccination in subjects born after 1974
• Also the neutralizing titers against MPX rise slowly and to limited extent.

Conclusion of the authors: As the role of MPXV neutralizing antibodies for protection against disease and transmissibility is currently unclear and no correlate of protection against MPXV infection has been identified yet, this raises the question how well vaccinated individuals are protected?

Ep 288-20: Ilchmann medRixv 9 Sept 22 is more positive about MVA-BN (especially after a booster):  Single and 2-dose vaccinations with MVA-BN® induce durable B cell memory responses in healthy volunteers that are comparable to older generation replicating smallpox vaccines.

Abbreviations: BD = booster dose; ELISA = enzyme-linked immunosorbent assay; GMT = geometric mean titer;

HSPX+ = history of smallpox vaccine positive; N = total number of participants per group; PBO = placebo;

PRNT = plaque reduction neutralization test.

The primary vaccination (initial study left) results in a temporary rise in neutralizing Ab that return to baseline in the MVA vaccinated subjects after 2 years (108 weeks), while titers remain somewhat higher in those who historically received a vaccinia.

However, after a booster in the MVA vaccinated 2 years earlier (right follow-up study) the neutralizing titers rise very rapidly to levels that are higher than after the initial vaccination.

Conclusion of the authors: The observed anamnestic responses, in the absence of sustained detectable nAbs (before boost), support the presence of durable immunological memory following MVA-BN immunization

CONCLUSION:

• The macaque model showed that MVA-BN is a promising vaccine against MPX
• The neutralizing Ab response in humans after a primary course of MVA-BN is rather weak (as compared to titers seen after COVID vaccination for instance), which is of some concern.
• A booster MVA-BN vaccine induces a rapid rise in neutralizing Ab, which is reassuring, if  the response after a booster mimics what happens after MPX infection.

Can we close the Monkeypox chapter for now?  We’ll see….

Best wishes,

Guido