Candidate vaccines and Therapeutics against Monkeypox infection

while human beings are still facing the challenges of the pandemic coronavirus disease (Covid-19), a new viral disease, monkeypox raises concerns among healthcare authorities about this new threat. Since May 2022, thousands of people have been affected by a continuous monkeypox outbreak linked to close contact transmission in numbers of nonendemic nations. The Food and Drug Administration (FDA) has not yet approved any medications to treat monkeypox in humans. However, medications created for smallpox patients, such as antivirals and other medical countermeasures, might also be effective against monkeypox. Tecovirimat (TPOXX), brincidofovir, cidofovir antivirals and vaccinia immune Globulin intravenous (viGiv) are the medical countermeasures for the treatment of monkeypox. The second and third generations of smallpox vaccinations have been developed after many years of research. Some of these vaccines may also be beneficial for monkeypox. Three vaccinations, MvA-Bn, LC16, or ACAM2000 can be used for monkeypox. Two of these (MvA-Bn and LC16) have received approval for the purpose of preventing monkeypox. Considering the current vaccine shortage, widespread immunisation is not advised. Therefore, prevention is the best policy to keep everyone safe. The current review highlights the treatment available for the management of monkeypox. it also reviewed the preventive measures that human beings should take to protect themselves from monkeypox infection.


inTRODuCTiOn
Monkeypox (MPOX) is a viral zoonotic illness, but human cases have been documented since 1970 and have become more common recently. 1Monkeypox virus (MPXV) is the doublestranded DNA virus of the Orthopox genus in the Poxviridae family.Orthopox virus is of the same genus as variola that is responsible for smallpox and vaccinia viruses that is used in the smallpox vaccine. 2 The 200-500 nm-sized double-strand DNA monkeypox virus is encased in a lipoprotein envelope.There are 190 open reading frames in the 197 kb monkeypox genome (ORFs).Additionally, it has been suggested that the immunomodulation process may be controlled by the monkeypox genome. 3Monkeypox got its name when it was first found in 1958 in colonies of monkeys kept for research.The decision to rename the illness is still being discussed with experts.Monkeypox is not as severe clinically as smallpox.According to a report by the WHO, 3-6% of cases of monkeypox result in death.Due to its potential to spread throughout the entire world, like the coronavirus, this illness is crucial to global public health.Dr Tedros Adhanom Ghebreyesus (WHO Director-General) declared monkeypox to be a public health emergency of international concern (PHEIC) on July 23, 2022.According to the International Health Regulations, declaring a PHEIC is the highest global public health alert level and can improve coordination, cooperation, and international solidarity. 4rior to 2022, Central and West Africa saw the most instances of monkeypox.However, a persistent outbreak linked to person-to-person transmission, first identified in May 2022, has affected thousands of people in several nonendemic nations.6][7][8][9] The virus of monkeypox can spread through aerosols.Monkeypox is less contagious than certain other infections as it can be transmitted only through close contact, including touching, kissing, and sex through any kind with an infected person.Children may get infected with monkeypox if they come into close touch with a person who is exhibiting symptoms.Monkeypox patients often develop a rash that is different, but it can also resemble that of several other viral illnesses like herpes simplex infection, varicella-zoster virus infection, secondary syphilis etc. 1,10,11 The WHO states that the smallpox vaccine might be used to prevent and treat monkeypox.However, research towards a particular monkeypox vaccination is ongoing.WHO is working with all the countries affected to enhance surveillance, provide guidance on how to prevent the spread, as well as provide medical care. 4

Treatment available for monkeypox
Many monkeypox patients have mild conditions and will recover on their own.However, some individuals might need to take painkillers for pain related to proctitis or tonsillitis.Stool softeners, topical lidocaine, and/or sitz baths must also be utilised for disorders like proctitis.For those who have or are at risk for dehydration (such as those with nausea, vomiting, dysphagia, or severe tonsillitis), those who need more intensive pain management, and those who are dealing with severe illness or consequences, supportive care requiring hospitalisation may be necessary.Treatment may still be beneficial for those who are immunocompromised and living with HIV.Tecovirimat, VIGIV, and brincidofovir, are currently available medical option from the Strategic National Stockpile (SNS) for monkeypox treatment. 12,13Cidofovir is available commercially for the treatment option. 4,13The management therapies for monkeypox are given in Table 1.

Antiviral therapy
There is currently no medication authorised, especially for the infection caused by the monkeypox virus.The antivirals used for smallpox patients may be helpful in treating monkeypox.Based on dose and safety studies in healthy individuals and animal models, antiviral medications were licenced for the treatment of smallpox, but it is predicted that they will work similarly against monkeypox.The preferred treatment now is tecovirimat. 10

Tecovirimat (TPOXX, ST-246)
The antiviral drug Tecovirimat has been approved by the United States Food and Drug Administration (FDA) against smallpox infection in both adults and children. 14For those with severe illness or those at risk of developing it, as well as those who have lesions in their eyes, mouth, or anogenital region, antiviral medication is advised.Despite the lack of clinical data, tecovirimat seems to be well tolerated and has the potential to decrease the length of infection and viral shedding.A clinical trial (STOMP) is currently being conducted to determine how well tecovirimat treats monkeypox. 15For pregnant and nursing women who are infected with monkeypox virus, the Centers for Disease Control and Prevention (CDC) advises antiviral treatment with tecovirimat.However, animal studies are the only source of information on the risks of tecovirimat to the foetus.In those experiments, tecovirimat was given orally to animals at doses that were roughly 23 times higher than those that are advised for humans.However, no specific foetal adverse effects were noticed. 16n children with monkeypox, tecovirimat treatment is necessary for those who have severe disease (airway obstruction, confluent lesions, encephalitis), consequences (cellulitis/ abscess, ocular lesions, pneumonia, or sepsis), and lesions involving anatomic sites that could cause the major outcome, such as scarring or strictures (e.g., infections involving the eyes, face, or genitals).Children under the age of 8, children suffering eczema and other skin diseases, and immunocompromised children should all be given the option of receiving antiviral medication10.Alternative medications, such as cidofovir or vaccinia immune globulin, must be chosen on case basis.If tecovirimat is unavailable, a person must decide whether to treat with an alternate drug such as cidofovir (or brincidofovir, if available), because these drugs carry a higher risk of side effects (eg, renal failure, electrolyte abnormalities) 10.][19][20][21][22] In addition to tecovirimat, eye drops or ointments containing trifluridine (or vidarabine) can be used to treat monkeypox lesions that affect the eye or lids. 23Tecovirimat has generally been well tolerated in people with monkeypox. 24In an expanded safety experiment that was conducted on about 360 human volunteers as part of the approval procedure, tecovirimat was given, and the results showed that the adverse effect profile was comparable to that of a placebo. 25Headache, nausea, and abdominal pain are the side symptoms that are most frequently mentioned.In a study on 255 patients who got tecovirimat, the median time to subjective benefit after beginning medication was three days. 24In a different group of seven monkeypox patients, the one who had tecovirimat treatment had a shorter duration of disease and virus shedding than the others, including several who received brincidofovir. 1 Its efficacy during the ongoing monkeypox outbreak is being investigated in a randomised experiment. 26The majority of tecovirimat evaluation studies conducted before the 2022 monkeypox outbreak were conducted on animal models, and tecovirimat protected nonhuman primates from lethal monkeypox virus infections. 16

Cidofovir
Cidofovir (Vistide), is an injection-based antiviral drug that has been given FDA approval for treating cytomegalovirus (CMV) retinitis in AIDS patients. 16The effectiveness of cidofovir against monkeypox infection in humans is not known.][29] Cidofovir treatment may be considered in cases where a patient has a severe monkeypox infection, although the treatment benefits are not known.Its use can cause significant negative effects, such as nephrotoxicity. 16

Brincidofovir (CMX001 or Tembexa)
Brincidofovir is an oral prodrug of cidofovir.The safety profile of brincidofovir may be better than that of cidofovir.In contrast to cidofovir treatment, serious renal damage or other side effects have not been reported when treating cytomegalovirus infections with brincidofovir.It is not advisable to use brincidofovir and cidofovir together. 16Brincidofovir was authorised for use in the United States in June 2021 to treat smallpox. 30It is accessible via the FDA's emergency investigational drug (EIND) programme.There are few documented studies on the effectiveness of this antiviral drug against monkeypox virus.][33] However, three monkeypox patients were given brincidofovir (200 mg once weekly orally) and all three experienced increased liver enzymes, necessitating the cessation of treatment. 1linicians who request and acquire an FDA-approved single-patient emergency use IND (e-IND) are permitted to access brincidofovir from the SNS for the treatment of monkeypox.People with positive test findings for the human monkeypox virus who have severe disease or are at high risk for progression to severe disease will be taken into consideration for the FDA's review criteria for brincidofovir e-IND requests for treating monkeypox infections in people. 16ccinia immune Globulin intravenous FDA has granted Vaccinia Immune Globulin Intravenous (VIGIV) a licence to be used in the management of vaccinia vaccination-related side effects.However, treating monkeypox with it is not permitted.As a result, the CDC has an expanded access IND protocol that permits the use of pre-stocked VIGIV for the treatment of orthopoxviruses, including monkeypox, during an outbreak.There are no accessible data on the effectiveness of VIGIV in treating human infections with the monkeypox virus.It is uncertain whether VIGIV therapy will help a patient with a severe monkeypox infection.However, medical professionals may consider its use in serious conditions when the production of a strong antibody response may be inhibited.VIGIV can be used as a preventative measure in exposed individuals with significant immunodeficiency in T-cell function when smallpox or monkeypox vaccination is not recommended.The United States Government does not have VIGIV prepositioned.On a case-by-case basis, CDC will provide it upon clinician request.16,34 vaccine for monkeypox Mass immunisation cannot be possible for healthy person in this monkey epidemics.First-generation vaccines are smallpox vaccines created and effectively used at the intensive smallpox eradication program (SEP) in contrast to smallpox vaccines created after the end of the eradication phase or subsequently and made using modern cell culture method.Second-generation vaccines are smallpox vaccines produced using the same strain of vaccinia virus that is used in first-generation vaccines, or clonal virus variations plaque-purified from conventional vaccine supplies and produced on specified cell lines.Third-generation vaccinations are those that have undergone additional passages in cell culture or animals, and were especially created as safer vaccines like LC16 and MVA-BN towards or after the eradication phase conclusion.35 Three vaccinations, MVA-BN, LC16, or ACAM2000 can be taken into consideration for approved or off-label indication for the prophylaxis (pre and post-exposure) of monkeypox.Two of these vaccines, MVA-BN and LC16, have received approval for the purpose of preventing monkeypox.However, only the persons who are at risk and has had close contact with monkeypox infected patient should get the vaccine.At present, widespread immunisation is not possible.36 The live vaccinia virus in vaccines that are slightly replicating (like LC16 from KM Biologics) and nonreplicating (like MVA-BN from Bavarian Nordic) has been greatly attenuated and has improved safety profiles.These vaccines produce antibodies against orthopoxviruses.36 Newer and safer vaccines that have been created for the smallpox, which has been eradicated.may potentially be beneficial for monkeypox.Smallpox vaccine has been shown to be protective against monkeypox in the past.However, currently, no clinical information is available on the effectiveness of modern vaccines for smallpox/monkeypox.4 The need-risk-benefit analysis for vaccine selection should consider the safety, reactogenicity, and risk of vaccination-related adverse events.Replicating vaccinia-based vaccinations (like ACAM2000 or other vaccines created using cell culture method), minimally replicating vaccines (like LC16), or non-replicating vaccines (like MVA-BN) may be considered for healthy people.A particular non-replicating monkeypox vaccine like MVA-BN would be chosen for people for whom a regular replicating vaccination (such as ACAM2000) is contraindicated due to immunological deficiencies, immunosuppressive therapy, or atopic dermatitis.When pre-or post-exposure vaccination is being considered for women during pregnancy or breastfeeding, MVA-BN, a non-replicating or LC16, a minimally replicating vaccines are preferable.If vaccination for post-exposure prophylaxis is being considered for children, non-replicating (MVA-BN) or minimally replicating (LC16) vaccines are preferred.36 LC16 and MVA have received emergency use permission for children in Japan, and USA, respectively.35 The vaccines currently on the market for monkeypox are listed in Table 2, along with their regulatory status.In order to prevent disease onset or lessen its adverse effects, persons in close contact with infected patients are advised to get post-exposure preventive vaccination (PEPV) with second or third-generation vaccine, within four days of first contact (and within 14 days if no symptoms appear).As suitable and accessible, PEPV can be given along with any of the vaccinations indicated in Table 2.The timing of vaccinations varies per product.

JYnneOS® (MvA-Bn) vaccine
JYNNEOS (MVA-BN) is an authorised vaccine to prevent both smallpox and monkeypox.It is the main vaccination being used to combat the monkeypox outbreak.MVA-BN® (Modified Vaccinia Ankara -Bavarian Nordic) is a patented and exclusive vaccination platform technology of Bavarian Nordic. 37An attenuated (weaker) form of the vaccine virus is known as modified vaccinia Ankara (MVA).It is used as a vaccination against smallpox and monkeypox and is known as MVA-BN.The two-dose MVA-BN (JYNNEOS®, USA; IMVANEX®, Europe; IMVAMUNE®, Canada) was authorised by the European Medicines Agency EMEA/H/C/002596 in 2013 and the U.S. Food and Drug Administration (FDA) on September 24, 2019.It is now indicated for preventing smallpox and monkeypox (MPXV) diseases in adults who have been found to be at high risk for infection.Its brand names are IMVANEX® in the Europe, IMVAMUNE®, in Canada, and JYNNEOS®, in the US.It has less adverse effects than the conventional smallpox vaccine.Based on this live, attenuated vaccinia virus (MVA), MVA-BN vaccine can induce a strong immune response even though it cannot replicate in the human body. 38The JYNNEOS (MVA-BN) vaccine is cultured using chicken embryo fibroblast cells and a media devoid of serum.There are several processes used to purify and filter it out of the cells, including benzonase digestion.9][40] Regarding the effectiveness of the vaccine, recent studies have shown that MVA-BN stimulated a response even in people who already had immunity to vaccinia.This response included high cellular activity and a humoral (antibody) immune response about ten days after the second dose.On November 22, 2022, the UK Health Security Agency released its prediction of vaccine effectiveness for a single dosage at 78% 14 or more days following immunisation. 4he JYNNEOS vaccination is approved for two doses spaced 28 days (4 weeks) apart.The Jynneos vaccination can be given intradermally, in a layer extremely close to the surface of your skin, or subcutaneously, in the fat beneath your skin.The FDA-approved dosage regimen is the accepted protocol.In the standard regimen of subcutaneous (Subcut) form of administration, a 0.5mL injection volume is administered.The standard regimen has also been approved for people<18 years since August 9, 2022, under an Emergency Use Authorization.The vaccine is administered subcutaneously by injecting it into the fatty tissue, commonly over the triceps in children and adults older than 12 months of age or in the anterolateral thigh in infants and toddlers less than 12 months.
Under the terms of an Emergency Use Authorization that was given on August 9, 2022, an alternative regimen may be utilised in the context of the current national Public Health Emergency (PHE) for individuals age > 18 years.A 0.1mL injection volume is administered through the intradermal (ID) route of administration as a permitted alternative regimen.An intradermal vaccine recipient should manifest "a visible pale elevation of the skin" known as a wheal.
A clinical study's findings demonstrated t h at t h e l owe r i nt ra d e r m a l d o s e wa s immunologically equivalent to the regular subcutaneous dose. 41MPOX vaccinations can protect person from the disease, but not right away.The maximum level of protection against MPOX is provided by receiving two doses of Jynneos.Approximately two weeks after receiving their second JYNNEOS shot, a person is deemed fully protected. 38YNNEOS may often be given without consideration to the time of most other vaccines because it is based on live, attenuated, non-replicating orthopoxvirus.This covers the concurrent administration of JYNNEOS and other vaccines, such as the influenza shot, but at different body site.When giving the COVID-19 vaccination, there are additional factors to consider.(Interim Clinical Guidelines for the Administration of COVID-19 Vaccines).There is no requirement that patients who have previously had the received COVID-19 vaccine wait a certain amount of time before receiving the orthopoxvirus vaccine (either JYNNEOS or ACAM2000).The Jynneos vaccine will be accessible to most HIV-positive patients. 4

ACAM2000
ACAM2000 is a replication-competent smallpox vaccine that can be given to only a few people.Emergent BioSolutions currently manufactures the ACAM2000 vaccine.ACAM2000 vaccine includes the contagious Vaccinia virus, a live virus that can infect other persons.The vaccinia virus is of same virus family as that small or monkeypox viruses therefore, it can be used in protecting humans from monkeypox infection.ACAM2000 has a higher rate of side effects than the MVA vaccination.It has been given approval in the US to prevent smallpox.A CDC-approved expanded-access investigational new drug (EA-IND) application approve its usage in treating monkeypox.It is an alternative to the JYNNEOS vaccine. 1,4,36,42,43ACAM2000 effect against monkeypox is uncertain, but one study suggested that its precursor Dryvax, smallpox vaccine (the first-generation), showed protection against monkeypox among 1555 vaccinated contacts of 338 patients in the Democratic Republic of the Congo (then known as Zaire). 44The evidence for immunogenicity is moderate. 45ACAM2000 is derived from a clone of the previously used vaccine "Dryvax."Like the previous "Dryvax" vaccine, ACAM2000 should not be given to individuals who are immunocompromised or pregnant since it can induce pericarditis and myocarditis.The ACAM2000 is the first vaccination to have a medication guide approved by the U.S. Food and Drug Administration, with a screening protocol prior to injection. 46For individuals aged 1 and older who have been shown to be at high risk for infection, the CDC suggests that immunisation with ACAM2000 can be taken into consideration to prevent monkeypox.It is recommended to administer the ACAM2000 vaccination in a single dose by repeatedly pricking the skin, often on the upper arm.Individuals are deemed to be fully protected after four weeks of getting ACAM2000.Simultaneous immunization is not advisable after getting the ACAM2000 vaccine.If a person receives the ACAM2000 vaccination, a live injectable vaccine such as the MMR or varicella vaccine (chickenpox) should not be given on the same day.
There should be at least 28 days between them and the COVID-19 injections may be postponed by 4 weeks. 4

LC16 KMB
LC-16 is a third-generation live attenuated vaccine against minimally replication-competent vaccinia virus (LC16m8 strain) approved in Japan. 1 LC16 KMB (LC16m8) was developed by the Japanese company KM Biologics as a smallpox and monkeypox freeze-dried cell culture vaccine.KM Biologics (SVRG Kaketsuken) is a unit of Meiji Holdings, a Japanese food, and pharmaceuticals corporation with headquarters in Kumamoto, Japan.It was approved for use in Japan in 1975 for people of all ages and was granted a licence in the United States under the emergency investigational new drug programme.The government of Japan has not offered smallpox immunisation to the public since 1976.On August 2, 2022, 47 LC-16KMB was authorised by the Ministry of Health, Labour, and Welfare (MHLW) of Japan for pre-exposure prophylaxis (PrEP) for the monkeypox virus.After assessment by the advisory committee, this consent was given.A notification of additional approval of the indication for "Monkeypox Prevention for "LC16 KMB" was made public by Meiji Holdings on August 3, 2022.The National Agency of Drug and Food Control in Indonesia is examining authorisation as of August 31, 2022. 48 2017 49 study found that LC16m8 vaccination of people produced neutralising antibodies against smallpox virus, and the impact was same to that of the ACAM2000 smallpox vaccine.
The Lister vaccinia smallpox vaccine, designated LC16m8, was modified for cell culture attenuation and lacked the B5R protein.LC16m8 preserves most of the vaccinia genome in contrast to replication-deficient vaccines like Modified Vaccinia Ankara.Therefore vaccination recipients may develop a "take lesion" due to its replication at the inoculation site. 1,36,50An immunosuppressed person, who suffers from atopic dermatitis, is pregnant, or has had an adverse reaction to any vaccine component should take the LC16 vaccine with caution.Administrators of the vaccine and healthcare professionals must be equipped to handle any anaphylactic reaction that may occur after LC16 administration.Following the administration of the LC1618 vaccine, patients may have mild side effects such as lymphadenopathy, fatigue, joint pain, rash, erythema at the inoculation site, fever, swelling at the inoculation site, and autoinoculation.Compared to those who received a booster shot, primary vaccination recipients experience far more side effects.There have been no recorded severe adverse effects.The conventional scarification technique is used to deliver LC16m8 in a single dosage.The strong store stability of LC16m8 was proven by its longterm storage stability for formulation i.e., 10 years and for drug substance i.e., 5 years. 36,50

Prevention against monkeypox
The danger of monkeypox transmission in public places and healthcare facilities can be reduced by implementing infection prevention and control strategies.Vaccination is one such important strategy.It requires a few weeks to develop immunity after getting vaccine, and it is not known yet that how well the vaccines provide protection to the person or if vaccine prevent persons from spreading infection to others because their monkeypox efficacy data is limited.However, considering the present vaccine shortage, individuals must temporarily alter some habits that can make them more susceptible to infection.Until there is an adequate supply of vaccines, this short-term precaution will help in slowing the monkeypox spread.It is crucial that between the first and second dose the activities that put people at risk of contracting monkeypox between the first and second doses of the vaccine.The highest protection is achieved two weeks following the second vaccination dosage. 10 person infected from monkeypox should avoid kissing, touching or vaginal, oral or anal intercourse to protect yourself and others if you or a partner has monkeypox or suspects they may have it.Avoid handling any rash in particular.
Habit of sharing thing of infected persons like towel, toothbrushes, sex toys and other personnel things should be discontinued.Monkeypox virus has been found in semen but the spreading of monkeypox virus through semen or vaginal secretion is still not known.
Person of any gender or sexual orientation, can develop MPOX.The most vulnerable are those who engage in sexual activity with numerous or new partners.Cisgender guys who have intercourse with men and their sex partners are particularly affected.Although there is little information available, anyone who might be involved in queer sexual networks should be aware of the effects of MPOX on trans and non-binary individuals. 51

COnCLuSiOn
Monkeypox is a viral disease that spreads through close contact with an infected person.At present, no specific treatment is available for monkeypox.The treatment available for smallpox is considered for the management of monkeypox.Vaccines are not available for mass immunization.There is an urgent requirement to develop a specific treatment to combat this disease.

Table 1 .
The management therapies for monkeypox Therapeutic agents

Table 2 .
WHO Vaccine choice for monkeypox per 24 August 202235