An overview on Monkeypox, Current Paradigms and Advances in its Vaccination, treatment and Clinical Management: trends, Scope, Promise and Challenges

Monkeypox virus is an orthopoxvirus sharing the common genus with variola and vaccinia virus. Most of the monkeypox (MPX) cases had been reported from the central and west African region (the main endemic areas) prior to 2022 but there was a sudden outbreak in May, 2022 disseminating the infections to thousands of people even in non-endemic countries, posing a global public health emergency. MPX was considered a rae and neglected disease, however the 2022 MPX outbreaks in multiple countries attracted attention of worldwide researchers to pace up for carrying out researches on various aspects of MPXV including attempts to design and develop diagnostics, vaccines, drugs and therapeutics counteract MPX. Apart from being a zoonotic disease, the current outbreaks highlighted rapid human-to-human transmission of MPXV, besides the reverse zoonosis has also been documented with recent first report of human-to-dog transmission, urging a call for the importance of one health approach. Atypical and unusual disease manifestations as well asymptomatic MPXV infections have also been observed during 2022 MPX outbreak. the affected patients typically develop a rash resulting in a mild disease followed by recovery with some supportive care and use of antivirals such as tecovirimat, cidofovir and brincidofovir in severe disease cases. Modified vaccinia Ankara (MVA) vaccine with an excellent safety profile has been recommended to patients with higher risk exposure and immunocompromised individuals. Moreover, another vaccine the replication-competent vaccine (ACAM2000) could be a suitable alternative to MVA’s non-availability to some selective immunocompetent individuals. Current review highlights the salient aspects of management and treatment of monkeypox along with underlying promises in terms of therapeutics and a variety of challenges posed due to current global public health emergency situation to counteract MPX.


INtRODuCtION
The monkeypox virus (MPXV) is a double-stranded, deoxyribonucleic acid (DNA) orthopox virus of the Poxviridae family, that causes Monkeypox (MPX), and has been known to have a close association with smallpox.MPXV firstly was identified among crab-eating macaques, during a laboratory outbreak of vesiculopustular skin eruptions in Denmark in 1958. 1 Further MPXV disease outbreak occurred in the Rotterdam Zoo in the year 1964, followed by in the year 1970 some more MPVX cases were identified in Central and Western Africa, among the children with mild fever, vesiculopustular rashes and lymphadenopathy symptoms.Subsequently, the cases of the virus constantly increased from hundreds to thousands across Congo Basin.The isolation of virus from animals was done firstly in the year 1985 from African squirrel in the Equatorial region of the Democratic Republic of the Congo followed by another case where MPXV was isolated in year 2012 from rainforests of the Ivory Coast; from dead baby primate of a monkey species which is known as "mangabey". 2,3ater in the year 2003, the cases of MPXV have been reported in Midwest US, where the disease outbreak was linked to pet prairie dogs.These dogs were imported from African rodents' resultant of cross-infection. 4Prior to year 2022, the MPXV disease was typically identified only to a few of the areas (Central/Western Africa) around the globe, however, in May 2022, the United Kingdom (UK) reported several MPXV disease infections to humans even without any clear history of travel or any animal links to these already reported areas. 5In the US alone, more than 5,000 cases were reported in June 2022 itself. 6Additional cases of the disease were reported thereafter in over multiple non-endemic countries in subsequent months due to rapid human-to-human transmission across many counties in the world.Presently as of December 16, 2022, around 82,809 confirmed disease cases (human infections) had been reported from 110 countries and locations, with 65 deaths. 7,8n West and Central African countries, MPX has replaced smallpox as the leading cause of human Orthopoxvirus infection since the 1980s.As such, it is crucial to have a firm grasp of the primary risk factors that contribute to the propagation of current outbreaks. 9Risk factors for the spread of the virus between humans include close physical contact, such as sleeping in the same bed or room, or sharing eating and drinking utensils.The risk of contracting zoonotic MPX increases when you spend time in the woods, whether you camp there or call it home.Interesting to note is that aiding a patient with hygiene and laundry has not been associated to an increased risk of spreading MPX. 10,11According to the World Health Organization (WHO), coming into physical contact with an infected individual is the most significant risk factor for contracting MPX.The danger of infection for those caring for the sick and their loved ones consequently increases.The World Health Organization (WHO) has acknowledged that this virus can be spread by unprotected contact with the flesh, blood, or other organs of ill or deceased animals.Risk factors for infection with MPXV include a lack of smallpox vaccination. 12,13It is possible that males are more at risk of catching the disease than females because they engage with wild animals more frequently in regions where the disease is endemic.MPXV is related to smallpox, although not in the same way.The smallpox vaccine has been proven to provide cross-protection against the MXPV at a rate of approximately 85%. 14 According to recent statistics, MPX has become more common since the smallpox vaccination program was discontinued.The decline in immunity and the growing deforestation of endemic areas are two other possible explanations for the MPX spike.The potential resurgence of MPX zoonosis has been linked to the evolution of the virus. 15he transmission of virus occurs from individual to individual by close contact with lesions, body fluids, respiratory droplets etc. Oral and nasopharyngeal fluid exchanges are also the cause of spread of virus which rapidly replicates at the inoculation site with spreads to the lymph nodes.Endemic MPX virus infection is usually selflimited, with the clade-dependent case fatality rates ranging from 1-10%. 16In general, the start of the disease takes place with fever, headache, body aches (muscle, backache) followed by fatigue. 17,18Phylogenetically, MPXV has two clades; one is the West African clade and the other one is the Congo Basin clade, which is also known as the central African clade. 19In Phylogenetic analyses, it has been reported that MPXV has circulated to some other areas where the virus has remained endemic. 20,21he present article presents an overview on monkeypox virus (MPXV) and the clinical disease (MPX), with a special focus on advances in vaccines and vaccination, drugs and therapeutics being made for management of patients for counteracting MPX outbreak.

epidemiology of monkeypox and underlying etiological factors
MPXV infection is one of the most significant orthopoxvirus infections reported ever since the smallpox infection was eliminated about four-decades back.First report of the virus isolation was reported way back in the year 1958 in monkeys having pox-like disease in them while in humans the monkeypox disease was discovered in the year 1970. 11The story dates back to the year 1968 in the Democratic Republic of Congo (DRC) which became completely free of smallpox, even then a boy around 9 years of age was diagnosed with the monkeypox disease.Since then, the cases of human monkeypox spread to more than 11 African nations showing an upward trend especially in the central and western regions of Africa along with rain forest areas of the Congo Basin in DRC. 22United States of America was the first country outside Africa to report the first MPX outbreak with over 70 cases reported in the year 2003 which supposedly came through contacts with pet prairie dogs suffering from the disease as these pets were kept with dormice and pouched rats that were imported from Gambia.The MPX disease recently has been reported in travelers from African nations to Israel and the UK (September 2018; December 2019; May 2021; May 2022), Singapore (May 2019), and the United States of America (July 2021 and November 2021) (World Health Organization, 2022. 23PX was considered as a neglected disease prior to the current year, however its larger outbreaks have been reported most recently in May 2022.The first incidence of the current outbreak was discovered in a patient from London on May 6, 2022, who had recently travelled to Nigeria (where the disease is endemic).The UK Health Security Agency (UKHSA) later identified four new cases on May 16 that had no connection to travel to a nation where MPC is an endemic disease.Cases began to be recorded from an expanding number of nations and areas starting on May 18, primarily from Europe, then in North and South America, Asia, Africa, and Oceania. 24Brazil announced the first death outside of endemic Africa on July 29, 2022, involving a 41-year-old man with underlying comorbidities (F, 2022).On the same day, a 44-year-old man in Alicante became the first person to pass away in Spain.His cause of death was encephalitis brought on by infection with MPX.On July 30, 2022, Spain reported the death of a 31-year-old male in Córdoba from MPX-related infection.This man also had encephalitis. 25A 22-year-old man who passed away from MPX in Thrissur, Kerala, on July 30 was India's first verified case on August 1, 2022. 26The crucial aspect of the current MPX 2022 epidemic is that multiple countries are still reporting cases of MPX while cases have been recorded significantly from nations where the illness was not endemic and thus has expanded significantly outside endemic regions of Central and West Africa.For the first time, several MPX cases and clusters have been reported simultaneously in endemic and non-endemic nations across extremely dissimilar geographic regions.Tedros Adhanom Ghebreyesus, the director-general of the World Health Organization (WHO), recognized the urgency of the situation and declared the outbreak, a public health emergency of international concern on July 23, 2022.(PHEIC).
The major signs include a rash that looks like a pimple or blister and flu-like symptoms like fever, tiredness, and enlarged lymph nodes.People can exhibit only a rash and no flu-like symptoms, or the opposite may occur.In the current outbreak, cases frequently appear with genital or anus lesions, occasionally with penile enlargement or rectal pain, or proctitis. 27Lesions can also develop on hands, feet, cheeks, and other body regions.Within three weeks of infection, symptoms typically start to show.Eventually, the lesions scab up and peel off; this typically takes from two to four weeks.Multi-origins and complex virus transmission routes along with atypical and unusual disease manifestation as well as asymptomatic MPXV infections have also been reported during the current 2022 MPX outbreaks, hence greater measures for checking its transmission and adequate prevention and control strategies are suggested. 28,29PX is a zoonotic pathogen, 30 and more recently the first report of human-to-dog transmission of MPXV 31 has highlighted risk of reverse zoonosis of the virus, which calls for increasing the screening of different animal species including pets, adopting advanced global surveillance system, and strengthening of one health approach for effectively countering MPX transmission and circulation.[32][33][34][35] Various wild animals, including monkeys and rodents (such as squirrels, rats, and dormice), can spread the virus to people by bites or scratches; through activities like hunting, trapping, skinning, cooking, or ingesting infected animals; or through contact with infected bodily fluids 36 Human-to-human transmission, which mostly occurs through direct skin-to-skin contact with infectious sores, is less common than animal-to-human transmission but has occasionally resulted in small-scale, confined human outbreaks. 12Direct contact with infected skin lesions, mucocutaneous lesions, and respiratory droplets is required for humanto-human transmission (and possibly short-range aerosols requiring prolonged close contact).Transmission through fomite can also happen (for example, through infected clothing or linens). 37Although the virus can spread during sexual activity, MPX is not regarded as a sexually transmitted infection because it can also be contracted without having sex.38 It is also unknown if the MPXV may spread through semen, vaginal fluids, urine, or faeces, despite the fact that the virus has been found in semen.39 When a woman is pregnant, transmission to the fetus may happen via the placenta.40 It is uncertain if people without skin lesions can spread the virus or how frequently the virus is disseminated by respiratory secretions. Casua contact does not spread the infection.41 MPXV is a double-stranded DNA virus, though in the past it was thought to be RNAbased given to the presence of MPXV RNA showing significant amounts of human beta-2microglobulin (β2M) RNA.In some of studies, it has been reported that the presence/detection of β2M from either wastewater or from excretions of certain organisms showed the presence of nucleic acids within human cells.42 Upon the exposure of MPXV-infected human cells into wastewater, revealed the presence of MPXV RNA.In a study, the extraction was performed using a specialized type of polymerases [Volcano 2nd Generation (V2G)] that is capable of amplifying both DNA and RNA templates.43,44 In another study, the MPXV RNA detection was carried out from wastewater treatment plants.The obtained samples were amplified using qPCR, and the sequencing studies were performed.The sequences thus obtained were used in performing alignment studies, which revealed that the query sequence obtained had similarity to MPXV genome.45,46 The natural reservoir of the monkeypox virus is still unknown, though some of the rodents have been acknowledged to be naturally susceptible to the disease (MPXV). 33

Symptomatic trial and clinical management
The incubation period of the virus is usually 6 to 13 days long but in some of the cases it has been observed from 5 to 21 days.The disease is contagious from 1-2 days prior to the rash until when all of the scabs have fallen off or become pus-filled.The virus transmission in humans occurs primarily through direct contacts such as respiratory droplets, body secretions or lesions or through contaminated clothing or linens of an infected person. 11In animals, the transmission occurs by bite or scratch of infected animals. 47nitially, the cases observed for the disease investigation were as follows: a single person of any age group with a travel history to the affected countries within the last 21 days presenting with unexplained acute rashes and one or more of the symptoms including mild fever with headache, body ache with weakness, and swollen lymph nodes, etc. 48,49 Any individual who meets the case description for a suspected case, suffering from a clinically compatible condition, and has an epidemiological relationship. 50,51][54] The disease symptoms of MPXV lasts for about 2 to 4 weeks, the children are more likely to suffer from severe instances.The case fatality rates (CFR) of the MPXV disease have been known to fluctuate traditionally (from 0% to 11%) in the general population, with small children are likely to be more vulnerable.Recently, the CFR has been at 3-6%.General symptoms (fever, body ache, lymphadenopathy, sore throat & coughing etc.) last for about 5 days.In other series of symptoms, skin rashes start at day one and lasts for about 2-4 weeks. 55,56The skin rashes occur in different stages; initially in the stage-1, tongue and mouth lesions appear followed by centrifugal distribution within 24 hours. 57Specificity of rashes in the body includes as; 98% facial, 95% on palms and soles, 70% on oral mucous membranes, while 28% on genitalia and 20% on conjunctiva. 50,58By the end of 3rdday the lesions get grown/raised and fluid filled and last for about 1 to 2 days, which then turn into the pustule on 6 th or 7 th day of the infection.The lesions dry up by the end of the second week, the scabs last a week before dropping off. 59,60upportive treatment regimens for clinical management of MPX cases require rehydration with orally or intravenously administered fluids, hemodynamic balance, oxygen support, symptomatic case management and to tackle superinfections of bacterial skin lesions and eye complications. 11

Anti-viral Drugs and therapeutic interventions
Presently there is no as such approved treatment for the infections associated with MPXV.][63][64] The Food and Drug Administration (FDA) approved tecovirimat (TPOXX/ ST-246), a 4-trifluoromethylphenol derivative, against orthopoxviruses, has been recommended to be useful in treating MPX cases. 11,65Animal studies have indicated that this medication is effective against multiple orthopoxviruses, including MPX.Compassionate use of tecovirimat for vaccinia and cowpox was being conducted, and no concerning adverse effects were being observed. 66Tecovirimat inhibits the growth of the MPX virus envelope by inhibiting the production of the viral protein p37, which is highly conserved throughout orthopoxviruses.Those interested can have it in the form of capsules to be taken orally twice daily for a total of 14 days.On May 19, 2022, the US Food and Drug Administration greenlighted a solution for intravenous use. 67,68An extended access program for tecovirimat is currently being created for the Central African Republic, which is experiencing widespread MPX epidemics.
Brincidofovir is an antiviral medication for treating poxviruses that has been licensed by the European Medicines Agency and the FDA. 69Prairie dogs with chronic MPX infection exhibited a moderate survival benefit from this medication.In 2018, the first individuals in the United Kingdom were diagnosed with MPX, however neither brincidofovir nor tecovirimat were approved for use in treating the disease. 70n 2018, however, Brincidofovir was selected for the patients since it was readily accessible through an approved, urgent repurposing of an existing supply from a local clinical trial.A rise in hepatic transaminases, diarrhoea, nausea, vomiting, and stomach discomfort have all been recorded as adverse reactions to this medication. 8Pregnant women are not encouraged to take brincidofovir due to the risk of harm to the developing embryo or fetus.While cidofovir is also active in vitro for MPX, it is not a viable first-line treatment due to its high nephrotoxicity profile and electrolytic abnormalities.Another study, however, claims that cidofovir is more effective than the smallpox vaccine in treating fatal MPXV infections. 71For the treatment of cytomegalovirus, the Food and Drug Administration has just approved cidofovir.Cidofovir and brincidofovir both work by inhibiting viral DNA polymerase.To counter this, tecovirimat blocks a specific viral product to prevent intracellular viruses from escaping the cell. 39,66Vaccinia immune globulin intravenous (VIGIV) has also been found useful in treating severe cases of MPX as well as prospective passive antibody-based therapies such as hyperimmune globulin (HIG), monoclonal antibodies (mAbs), and convalescent plasma (CP) have also been suggested to play useful role for treating MPX, particularly beneficial against severe cases. 72he replicative cycle of MPOX virus in humans and the therapeutic interventions by the anti-MPX viral drugs have been elucidated in Figure .Tecovirimat, which is an orthopoxvirusspecific protein (VP37) inhibitor harbors the

Vaccines and Vaccination
JYNNEOS and ACAM2000 vaccines, the smallpox vaccines, are considered to be effective to treat MPX cases, with booster doses being more effective, which are presently being used as pre-exposure prophylaxis. 73Vaccinia-virus-based vaccines including current MVA-BN and ACAM2000 vaccines can elicit highly cross-reactive immunity against newly arrived MPXV. 74The use of Vacciniabased vaccines and anti-vaccinia immunoglobulin for post-exposure prophylaxis and management against MPX has also been highlighted. 75Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) is a live non-replicating third-generation vaccine, and is approved for both smallpox and MPX.The same vaccine in USA is marketed as JYNNEOSTM.This vaccination reveals about 85% effectiveness in protecting people suffering with MPX.However, in its overall effectiveness and safety against pregnant women is still in doubt.For the use of vaccination, the Disease Control and Prevention Center recommends vaccination for the MPX virus within four days of exposure.7][78] The smallpox vaccines are used for the treatment of MPXV, as these have been shown to be protective against the disease.These are genetically recombinant engineered products, in which some agents are encoded to produce antigens to the pathogens.These are made up of a live viral or bacterial vector.Even engineered vaccines are there in order to express a variety of exogenous antigens in the target cell cytoplasm.Few of the important vaccines, antiviral drugs and therapeutic agents used against monkeypox virus are presented in Table 2.
JYNNEOS vaccine so far looks like a safer option with about 85% efficacy against MPX, still we are not very clear about the stability,

Figure.
The replicative cycle of MPXV followed by the MPOX virus and putative mechanism of action of various drugs applicable at different levels.Whereas the drug Tecovirimat is an orthopoxvirus-specific protein (VP37) inhibitor that has a property of inhibiting the virus's systemic spread to other cells in the humans.Tecovirimat and cidofovir in combination work as DNA replication inhibitors which may provide synergistic effects efficacy and durability of the vaccine. 79Two-dose vaccination strategy and its ability to induce the immune response as well the long-lasting effects on immunity, still needs further evaluation in order to further decide the future course of action especially regarding the frequency of the booster doses.Although ACAM2000 has shown promise in trials but concrete data is required for JYNNEOS.Another challenge is about the efficacy and safety of the above vaccines for the lactating and pregnant women especially for the infants whether they are passively immunized. 79,80mmunization undoubtedly is going to hold the key as far as to minimize the MPX cases in humans and preferences to be given to healthcare professionals at high risk, immunodeficient individuals and young ones with impaired immune system.[86][87][88][89]

CONCluSIONS AND FutuRe PROSPeCtS
The need to reinforce measures targeted at preparing for an outbreak is urgent in light of the current knowledge gaps, the shifting epidemiology and clinical presentation of MPX, and other challenges.Increase in public health and disease monitoring infrastructures are urgently needed in all countries to combat the growing threat posed by emerging and re-emerging infectious diseases like MPX.For public health to be prepared and for priority research to be conducted, community-led, locally coordinated, interdisciplinary initiatives focused on capacity building and education are required.Those who work in healthcare's front lines and with the world's most vulnerable populations must be safeguarded in order to stop the spread of the current MPX outbreak.To effectively manage new or reemerging viral threats, it will be essential to implement proactive, continuous, comprehensive surveillance, quick risk assessments, response measures, early detection, and contact tracing.Increased attention to national healthcare systems and the creation of international laws, regulations, and response mechanisms are urgently needed in the wake of the COVID-19 pandemic.Due to poor health care infrastructure and scarce resources, MPX may go unreported in impoverished countries.Concerns regarding the potential for human-tohuman transmission of the disease are shared by members of the general public and healthcare professionals alike.Given the potential for a global pandemic, MPX illness is an issue of paramount public health importance that must not be dismissed.Understanding the dynamic epidemiology of this reemerging disease requires the detection and surveillance of MPX cases, which requires international cooperation.
To better treat and control this viral illness, more in-depth research into the disease and international collaboration are required.However, antiviral drugs, immunotherapeutics, and immunizations against MPX are not widely available at this time, thus there is a pressing need to get these treatments into the hands of countries reporting outbreaks.Although the prognosis for MPX varies depending on a number of factors such as immunization history, general health at the time of infection, and the presence of any preexisting medical disorders, in most cases, patients with MPXV suffer mild or self-limiting disease even without therapy.
In addition, there is a dearth of information from clinical trials on currently available MPX vaccines and antivirals.Current vaccinia vaccines, such as JYNNEOS, and antivirals, such as tecovirimat and brincidofovir, need more data from clinical studies to be fully effective.Though the emergency approval of the JYNNEOS for vaccination against MPXV is a major headway to contain MPX infection but still concrete research is desired as far as the overall efficacy of the vaccine is concerned along with assessing the side effects, risks and contraindications.Moreover, the duration of immunity following the 2-dose JYNNEOS vaccination series needs more investigation.It would also be helpful to get clinical data on the use of both the JYNNEOS and mRNA COVID-19 vaccines in tandem.Closer monitoring, vigilance of the situation along with enhanced surveillance, innovative treatment and control measures are the need of the hour so that effective and safer new generation anti-MPXV therapeutic agents could be developed.Specific reservoirs of the orthopox viruses need to be identified in order to be aware of the different properties of the virus and to know the high-risk behaviors for acquiring viral infections.It is vital to promote awareness among potentially impacted groups, healthcare professionals, and laboratory personnel in order to discover and stop future cases and successfully manage the present outbreak.Vaccines, medicines, and therapies that are both effective and specific against MPXV are urgently needed to aid in the control of the disease and in the clinical management of MPX patients.In brief, health systems need to raise public awareness, actively monitor for disease, diagnose patients quickly, and promptly report data in order to take any public intervention measures against MPXV's potential to cause an epidemic.

table 1 .
The chemical structures with structural features and possible mechanism of action of antiviral drugs (Tecovirimat, Brincidofovir, Cidofovir) against the monkeypox  Inhibition of Cytochrome P450 2C8 • Azatetracyclo moiety  Cytochrome P450 3A Inducer  Cytochrome P450 2C19 Inhibitor  Breast Cancer Resistance Protein Inhibitor Acyclic monophosphate nucleotide  Competing with dCTP analog of deoxycytidine (deoxycytosine-5-triphosphate) • 4-amino-2-oxopyrimidine for viral DNA polymerase • 3-hydroxypropan-2-yl]  May get incorporated into the • oxymethylphosphonic acid growing viral DNA strands. Prevent further DNA polymerization  Disruption of viral DNA replication Acyclic nucleotide analogue and  Competing with dCTP for viral lipid conjugate pro-drug of the DNA polymerase cidofovir  Incorporation into the growing • 4-amino-2-oxopyrimidine viral DNA strands.• 3-hexadecoxypropoxy  Prevention of further DNA • phosphinic acid polymerization • 3-hydroxypropan-2-yl  Disrupts DNA replication of viruses property of inhibiting the systemic spread of the virus to other cells in humans.Tecovirimat and cidofovir in combination has been shown as DNA replication inhibitors which could show synergistic effects as well.

table 2 .
Various vaccines and antiviral therapeutic agents used against the monkeypox virus