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Monkeypox

Monkeypox

Monkeypox is a viral zoonosis with symptoms similar to, but less severe than smallpox. Monkeypox was first discovered in 1958 when two outbreaks of a pox-like disease occurred in colonies of monkeys kept for research, hence the name ‘monkeypox.’

Overview

Monkeypox is a viral zoonosis with symptoms similar to, but less severe than smallpox. This disease, caused by Monkeypox virus infection, has two periods. The first period, is characterized by fever, headache, lymphadenopathy, myalgia and intense asthenia. The second period is characterized by skin rash that appears within 1-3 days of fever. Most people recover from monkeypox within a few weeks without the need for treatment but the disease can be more sever in young children, pregnant women and immunocompromised individuals. The incubation period for monkeypox is reported to be up to 21 days. Public health institutes recommend active monitoring and isolation/quarantine of close contacts for a minimum of 21 days after the last day of exposure.

Monkeypox virus is a member of the Orthopoxvirus genus, in the Poxviridae family of enveloped double-stranded DNA viruses that infect a broad range of animal hosts from insects to vertebrates. In addition to Monkeypox virus, other viruses of the Orthopoxvirus genus include Variola virus (smallpox) and Vaccinia virus (cowpox). Vaccinia virus was used as a vaccine for smallpox in humans after it was discovered by Edward Jenner in the late 18th century that milkmaids, exposed to cowpox, were resistant to smallpox. The word vaccine comes from vaccinia, which is derived from the Latin word vacca for cow. Smallpox vaccination is protective against other orthopoxvirus species including monkeypox. The reported increase in Orthopoxvirus infections, noted since around 2019, has been attributed to the discontinuation of routine smallpox vaccination after the eradication of smallpox.

Monkeypox primarily occurred in central and west Africa until an atypical monkeypox outbreak began in May 2022. Monkeypox endemic countries include Benin, Cameroon, the Central African Republic, the Democratic Republic of the Congo, Gabon, Ghana (animals only), Ivory Coast, Liberia, Nigeria, the Republic of the Congo, Sierra Leone and South Sudan. Animal hosts include rodents and non-human primates. The first monkeypox outbreak outside of Africa infected 70 cases in the United States in 2003. This outbreak was linked to contact with infected pet prairie dogs that had been housed with animals that were imported from Ghana.

Atypical monkeypox outbreak May 2022

An atypical outbreak of monkeypox was declared in the WHO European Region in May 2022. As of May 21, 2022 monkeypox had been reported from 12 WHO Member States that are not endemic for monkeypox virus. Non-endemic countries that reported monkeypox cases to the WHO between May 13 to May 21, 2022 are Australia, Belgium, Canada, France, Germany, Italy, Netherlands, Portugal, Spain, Sweden, United Kingdom and USA. The reported cases have no established travel links to endemic areas. Infected individuals have primarily included men who have sex with men and evidence suggests that the highest risk of infection occurs when there is close physical contact with someone with monkeypox while they are symptomatic.

As of June 6, 2022, about 800 cases of monkeypox were reported across over two dozen countries. The CDC reported global cases to be higher than 1000 over 29 nonendemic countries as of June 6, 2022 and raised the alert to level 2, which encourages people to practice enhanced precautions such as wearing face masks when traveling and avoiding close contact with sick people and sick animals. People with unexplained skin rash or lesions are urged to avoid contact with others and seek guidance from a healthcare provider.

On June 17, 2022 WHO removed the distinction between endemic and non-endemic countries when reporting on monkeypox. As of June 15, 2103 laboratory confirmed cases and one probable case, including one death were reported to WHO. 84% of confirmed cases were from the WHO European Region.

Monkeypox presentation in 2022 outbreak

Officials for the CDC and the WHO stated that many transmissions of monkeypox are not detected because the disease does not match descriptions in medical textbooks. Whereas textbooks show pox lesions covering a person from head to toe, people with monkeypox in the 2022 outbreak have presented with only a few localized lesions. Monkeypox may be misdiagnosed for common sexually transmitted diseases such as herpes or syphilis. Epidemiologist Jennifer McQuiston at the CDC said that doctors should suspect monkeypox in anyone with a new rash. Common presenting symptoms of monkeypox in the 2022 outbreak include genital and peri-anal lesions, fever, swollen lymph nodes and pain when swallowing. Guidance for clinicians on signs, symptoms and testing for monkeypox was distributed by the CDC Health Alert Network.

The milder lesions reported in the 2022 monkeypox outbreak are thought to reflect an incomplete picture of the spectrum of monkeypox illness, in which mild cases are not easily recognized. There is no evidence to suggest that a recent mutation in monkeypox, lead to a change in symptoms or mode of spread. Monkeypox is a DNA virus, which mutates and changes more slowly than RNA viruses such as SARS-CoV-2 which causes COVID-19. This is because DNA viruses are better at detecting and repairing mutations.

Monkeypox clades and evolution

Monkeypox virus was initially divided into two clades: The Central African strain/clade, also known as the Congo Basin strain/clade of monkeypox virus spreads more easily and cause more severe disease than the West African strain/clade. The West African clade of monkeypox has been reported to have a case fatality ratios of 1% and less than 1%. The Congo Basin/Central African clade has been reported to have case fatality ratios between 3-10% and more than 10%. Case fatality rate/case fatality risk/case fatality ratio/CFR refers to the proportion of people who die from a disease among those diagnosed over a certain period of time.

As of June 2 2022 only the West African clade of monkeypox had been detected in the atypical monkeypox outbreak in non-endemic areas, according to PCR testing. The WHO stated that the virus may have been transmitting undetected within nonendemic countries for weeks, months or possibly years before the May 2022 outbreak was declared.

As of June 3 2022, it was reported that two genetically distinct monkeypox variants, both belonging to the West African clade, were circulating in the US among the 30 total cases reported. Jennifer McQuiston of the CDC stated that the two strains likely stem from two different instances of the virus crossing over from animals to humans in Africa before spreading by person-to-person contact.

Since the May 2022 monkeypox outbreak three distinct clades of monkeypox virus are recognized. Clade 2 and clade 3 fall within the “West African” clade which causes less severe disease. Clade 1 is formerly known as the “Central African” or “Congo Basin” clade which is associated with higher fatality. The May 2022 outbreak is thought to have a single origin because all sequenced outbreak strains of the MPXV cluster together with similar sequence. The 2022 outbreak cluster is called B.1 which branches off from lineage A.1. The A.1 lineage was associated with the exportation of MPXV from Nigeria to the United Kingdom, Israel and Singapore in 2018 and 2019 and a large outbreak in Nigeria in 2017-2018.

The 2022 version of monkeypox virus has on average 50 nucleotide base changes, also called small nucleotide polymorphisms (SNPs), from the 2018-2019 monkeypox virus sequences. A research group from Portugal suggested that this branch may represent accelerated evolution since the rate of nucleotide changes is about 6-12 times more than expected for Orthopoxviruses, expected to have 1-2 substitutions per year. It was suggested that accelerated evolution of monkeypox virus could be driven by the action of APOBEC3, an enzyme that mutates viruses as a defense tactic. APOBEC3 forces mutations to occur during virus replication by deaminase and deaminase-independent mechanisms.

Mutations in the May 2022 outbreak monkeypox virus

The differences between the 2018 MPXV reference sequence and the 2022 MPXV outbreak virus include 3 amino acid changes (D209N, P722S, M1741I) in the immunogenic surface glycoprotein B21, a previously suggested antibody target. The UK government classified these three mutations as high priority. Inserting this version of the protein into non-virulent cowpox strains increased disease severity and mortality in rats.

The UK classified 4 mutations as medium priority:

  • S105L mutation in the C23L gene encoding a chemokine binding protein, which when deleted from rabbitpox virus increases disease severity in rabbits
  • S54F mutation occurs in the C22L gene, encoding a tumour necrosis factor (TNF) receptor-like protein. Deletion of a similar gene from ectromelia virus increases lung pathology in mice
  • D266N mutation occurs in the C19L gene, encoding an ankyrin repeat protein which has unknown function but may have a role in host range or virulence
  • E353K mutation in the F13L gene occurs in a target of the antiviral drug tecovirimat and tecovirimat resistance was conferred by a F13L protein mutation corresponding to the single nucleotide sequence change G277C. The F13L gene is involved in the production of enveloped orthopoxvirus virions.

The UK classified 2 mutations as low priority:

  • R48C mutation occurs in the C9L gene, encoding an antagonist of gene products stimulated by interferon that when deleted from vaccinia virus causes the virus to replicate worse in the presence of interferon
  • H221Y mutation occurs in the A46L gene, encoding a virulence factor gene that when deleted in vaccinia virus reduces virulence in mice
Antiviral drugs to treat monkeypox

Brincidofovir (Tembexa) is FDA approved for smallpox and considered safer than the smallpox drug cidofovir. Brincidofovir inhibits viral DNA polymerase and prevents DNA replication. Emergent BioSolutions bought the rights to Tembexa from

Chimerix for $225 million in May 2022.

Cidofovir (ST-246), is not FDA approved for smallpox or monkeypox. Cidofovir (Vistide) was FDA approved in 1996 for treatment of CMV retinitis in patients with AIDS and produced by Gilead, but was discontinued. The drug inhibits viral DNA polymerase and prevents DNA replication. The CDC holds an Expanded Access—Investigational New Drug Application (EA-IND) that allows for the use of Cidofovir for the treatment of orthopoxviruses (including monkeypox) in an outbreak.

Tecovirimat (Tpoxx), produced by Siga Technologies, is approved in Europe to treat monkeypox and approved by FDA for smallpox. The 2022 monkeypox virus has a mutation in the F13L gene and mutations in this gene are associated with resistance to tecovirimat.

Vaccinia Immune Globulin Intravenous (VIGIV; CNJ-016), manufactured by Emergent BioSolutions (previously Cangene) and another formulation manufactured by Dynport, is FDA licensed and indicated for treatment of complications due to vaccinia (smallpox) vaccination and aberrant infections induced by the vaccinia virus. The CDC has an EA-IND for use of VIGIV for treatment of orthopoxviruses including monkeypox in an outbreak. Cangene was awarded a contract by the CDC to deliver 100,000 treatment doses of VIGIV in 2002. VIGIV is a purified solution of the gamma globulin (IgG) fraction of human plasma from healthy individuals who have antibodies to the virus.

Vaccines to prevent monkeypox

Smallpox vaccines offer some protection against monkeypox. The majority of smallpox vaccines are live replicating (replication-competent) vaccinia virus (cowpox virus), which carry the risk of a vaccinated person infecting others with vaccinia. Immunocompromised people are vulnerable to complications from live replicating smallpox vaccines. MVA vaccines are derived from Modified Vaccinia Ankara, a strain of live vaccinia virus that does not replicate in human cells and are thought to be safer.

Attenuated vaccines are weakened forms of live virus or bacteria that cause an immune response in a recipient without causing disease. Attenuated vaccines can be generated by passing the disease-causing virus through multiple generations in cell cultures or animal embryos. Passaging viruses through non-human cells eventually produces a version of the virus that is specialized to that cell type and replicates less well in human cells. The resulting virus given as a vaccine is less likely to cause illness in humans but still provokes an immune response to protect against future infections. Part of vaccine development involves testing for neurovirulence, to choose a strain of virus that does not damage the nervous system.

In 1965, WHO established criteria and standards for smallpox vaccines which included reducing the virus derivatives that could be used for vaccine production to three strains: Elstree (Lister Institute, UK), EM63 (Moscow Research Institute of Viral Preparation, Russia) and the New York City Board of Health (NYCBH) strain VV (Dryvax ® , Wyeth Pharmaceutical, Inc., Philadelphia, USA and a smallpox vaccine made by Aventis Pasteur, Swiftwater, PA, USA). ACAM2000, JYNNEOS and APSV are the three smallpox vaccines in the US Strategic National Stockpile.

Live replicating vaccinia
ACAM2000

ACAM2000 is an attentuated live replicating vaccinia virus grown in cell culture derived from the NYCBH strain. ACAM2000 is manufactured by Emergent BioSolutions (aquired from Sanofi Pastuer Biologics, formerly Acambis) and is administered with a two-pronged stainless-steel needle dipped into the vaccine solution. The skin is pricked several times in the upper arm and the virus grows at the injection site, causing a localized infection or pock. The immunized person develops antibodies and immune cells that fight off smallpox and related infections such as monkeypox.

ACAM2000 replaced Dryvax and was FDA approved in 2007 for people at high risk of exposure to smallpox. ACAM2000 was found to be comparable to the Dryvax version, from which is was derived, in immunogenicity and protection against smallpox in animal studies. ACAM2000 is produced in cell culture, whereas Dryvax was prepared from discharged lymph material scraped from bovine calves infected with vaccinia virus. ACAM2000 was found to have less neurovirulence and cutaneous virulence compared with Dryvax. Clinical studies showed slightly attenuated vaccine-emergent reactions with ACAM2000. Clinical studies showed that myocarditis occurs in 1 in 175 adults who are vaccinia naïve.

Aventis Pasteur Smallpox Vaccine (APSV)

Aventis Pasteur Smallpox Vaccine (APSV) is replication-competent investigational vaccine expected to have a similar safety profile to ACAM2000. APSV would be made available under an IND or EUA for use in circumstances where ACAM2000 is unavailable, depleted or contraindicated.

LC16m8 and LC16m8Δ

LC16m8 is licensed for smallpox in Japan. LC16m8 was derived from the Lister Institute/Elstree strain of vaccinia, passaged (grown in culture) many times after which an attenuated phenotype was selected that was expected to cause less unwanted side effects. LC16m8 maintains replication at the site of inoculation and was shown to be less neurovirulent than unattenuated vaccinia strains. LC16m8 is manufactured by the Chemo-Sero-Therapeutic Research Institute (KAKETSUKEN) in Kumamoto, Japan. Some clinical development of LC16m8 was conducted by the US company VaxGen in 2004. The partnership for co-development of LC16m8 between Chemo-Sero-Therapeutic Research Institute and VaxGen was terminated in 2007.

The low neurovirulence profile of LC16m8 was reported to be comparable to replication incompetent strains of vaccinia virus. This vaccinia strain was found to spontaneously revert to a more virulent form. LC16m8Δ is a more genetically stable form, generated byh removing the B5R gene, that prevents the emergence of virulent revertants. In a mouse model, LC16m8Δ was found to have higher immunogenicity similar to Dryvax and superior to modified vaccinia Ankara.

Live non-replicating vaccinia/ MVA

Jynneos, produced by Bavarian Nordic, is approved in Canada and the US for monkeypox and used off-label in Europe for monkeypox. The Jynneos vaccine is derived from Modified Vaccinia Ankara (MVA) and is a live virus that does not replicate in humans. WHO recommended MVA to be given up to 14 days after exposure with the ideal time being within 4 days.

Live virus generated with synthetic biology
TNX-801

TNX-801, by Tonix Pharmaceuticals is a horsepox-based live virus vaccine generated by synthetic biology that is in preclinical development to protect against monkeypox and smallpox. Tonix Pharmaceuticals was issued a US patent for TNX-801 entitled ‘Synthetic Chimeric Poxviruses’. The patent includes claims covering the synthetic horsepox virus and for the company’s Recombinant Pox Virus (RPV) platform to develop vaccines against other pathogens such as SARS-CoV-2. Molecular analysis of DNA suggests that TNX-801 is closer to the smallpox vaccine discovered by Dr. Edward Jenner in 1978, obtained from lesions on cows with cowpox, than are modern smallpox vaccines.

TNX-801 was synthesized based on the DNA sequence of the 1976 natural isolate Mongolian horsepox clone MNR-763. Variolae vaccinae (cowpox) is thought to have originated in horse. Seth Lederman, Co-Founder and CEO of Tonix Pharmaceuticals collaborated with David Evans, professor at University of Alberta, Canada in the synthesis of horsepox virus for vaccine research, to develop poxvirus-based therapeutics and to promote public health discussions relating to synthetic biology. The publication of the synthetic biology-generated horsepox virus was controversial due to the risk the research could be misused to produce a bioweapon. There had been an ongoing debate about whether the last stocks of smallpox should be destroyed, but the synthesis of horsepox proved the feasibility of re-creating it in the lab.

Nucleic acid-based vaccines

4pox is a DNA-based vaccine that was shown to protect nonhuman primates against monkeypox virus-induced severe disease. 4pox targets virus surface protiens L1, A27, B5, and A33. 4pox was delivered into mice and nonhuman primates by gene gun or skin electroporation. 4pox was developed by Jay Hooper and colleagues at the US Army Medical Research Institute of Infectious Diseases (Fort Detrick, Mayland). Jay Hooper has a patent for DNA vaccines against poxviruses.

Inovio Pharmeuticals has a DNA medicines platform and worked on a smallpox vaccine with published results in 2010. The experimental DNA-based smallpox vaccine protected nonhuman primates against monkeypox in a challenge trial.

Moderna, the biopharma responsible which developed an RNA-based vaccine for COVID-19, announced on May 23, 2022 that it plans to work on monkeypox at a preclinical stage.

Diagnostic tests for monkeypox

As of June 5, 2022 the US has capability to process about 7000 orthopoxvirus diagnostic tests per week through about 70 labs in 46 states. Many diagnositic tests do not specifically test for monkeypox, but the family orthopoxvirus, of which monkeypox virus is a member. A positive orthopoxvirus molecular test may be assumed to be monkeypox during a monkeypox outbreak.

On June 22, 2022 the Department of Heath and Human Services through the CDC began shipping orthopoxvirus tests to five commercial laboratory companies which are Aegis Science, Labcorp, Mayo Clinic Laboratories, Quest Diagnostics and Sonic Healthcare, to increase monkeypox testing capacity and access.

Abbott Laboratories stated it is developing a test for monkeypox.

Becton Dickinson partnered with CerTest Biotec to produce the monkeypox virus molecular diagnostic test called VIASURE Monkeypox CE/IVD test. The test will use and be validated on the BD MAX system, an automated platform for nucleic acid extraction and real-time PCR. The test is reported to give results for up to 24 samples within three hours.

BGI Group, based in Shenzhen, developed PCR-based monkeypox virus detection kit.

Cepheid announced plans to develop a PCR test specifically for monkeypox in partnership with BioGX, a reagents company. Monkeypox PCR tests will be designed to run on the Cepheid's GeneXpert hardware.

Creative Biogene has a Monkeypox Virus Real Time PCR kit.

Daan Gene, based in Guangzhou, has a CE certified PCR-based detection kit for monkeypox virus.

Roche and subsidiary TIB Molbiol, developed three PCR tests for diagnosis of monkeypox. The three LightMix Modular Virus test kits use quantitative PCR technology and run on the company’s PCR analyzers. One test detects orthopoxvirus which includes smallpox, cowpox, horsepox and monkeypox. The second test detects the West African and Central African clades of virus. The third test identifies the presence of orthopoxvirus and whether it is either of the two monkeypox forms.

Sansure Biotech developed a monkepox virus nucleic acid diagnostic kit that has CE certification. The kits is compatible with fluorescence PCR and their iPonatic Molecular Diagnostic System for point-of-care testing (POCT) and COVID-19 molecular diagnostics platforms.

Shanghai Zhijiang Bio has a CE registered monkeypox virus nucleic acid detection kit which uses fluorescent PCR.

Tetracore is developing a rapid antigen test for monkeypox point-of-care testing. Results were published in 2013 on its test called Orthopox BioThreat Alert assay, which can be used outside the laboratory. The test is an antibody-based lateral-flow assay which labels and captures orthopox virus.

Trivitron Healthcare, a medical device company in India, developed a four-color fluorescence-based kit, reported to take an hour to complete.

Organizations and initiatives involved in the development of vaccines and treatments for monkeypox
CEPI

Coalition for Epidemic Preparedness Innovations (CEPI) is a global partnership between public, private, philanthropic, and civil society organizations working to accelerate the development of vaccines against emerging infectious diseases. CEPI is striving to enable equitable access to vaccines during outbreaks. CEPI is taking a prototype-vaccine approach, where broad vaccines can be quickly adapted to new threats as they emerge. Existing research in vaccine development can be used in their prototype-vaccine approach and applied to the approximately 25 viral families that are known to infect humans. Orthopoxvirus vaccines would be part of CEPIs planned library of vaccine candidates which are part of a $3.5 billion pandemic preparedness plan which establishes libararies of viruses ready to be adapted against new viral threats.

Companies working on Monkeypox

Timeline

June 6, 2022
The CDC raised Monkeypox to Alert - Level 2 - Practice enhanced precautions
May 2022
An atypical outbreak of monkeypox was declared in the WHO European Region following reports of a number of cases across several Member States not linked to countries where the disease is endemic.
2003
The Detection of Monkeypox in Humans in the Western Hemisphere
1970
Monkeypox was first reported in humans in the Democratic Republic of the Congo. A 9-year-old boy was infected in a region where smallpox had been eliminated in 1968.
1958
Monkeypox was initially discovered in monkeys in a Danish laboratory.

Further Resources

Title
Author
Link
Type
Date

CDC: 2022 United States Monkeypox Case

Web

HAN Archive - 00468 | Health Alert Network (HAN)

Web

June 14

Q&A: What you need to know about monkeypox

Web

May 26, 2022

References

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