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Monkeypox vaccines? Can we get things right this time?

Vaccines have been incredibly effective in reducing the burden of infectious diseases globally. Vaccines contribute to our increased life expectancy and have enabled us to live healthy productive lives. Clinical trials, observational data, implementation science and historic precedence have strengthened our understanding of the effectiveness of each vaccine and guided the development of guidelines on how, when and to whom the vaccine is administered. With each vaccine we determine the dose, route of administration, the correlates of protection, the optimal population to be vaccinated, the efficacy, vaccine effectiveness, and the duration of protection. Important questions such as these need to be answered when we vaccinate against any ‘new’ disease.

Monkeypox belongs to the same virus family as smallpox. It is endemic (meaning that it occurs commonly) in parts of West and Central Africa. Countries such as the Democratic Republic of Congo report 2000-3000 cases/year. It occurs in children and young adults and is spread by contact as well as respiratory droplets. Sporadic cases have been reported in non-endemic countries including an outbreak in the United States in 2003. This past year we have seen a striking increase in cases in Europe and North America. Although the disease has been mostly mild, there have been reports of severe complications including encephalitis and deaths. Mortality in endemic areas can be as high as 16%.

Smallpox vaccines can also be used for monkeypox. Smallpox was eradicated globally in the 1970s but ongoing concerns for bioterrorism have led to continued investments in improving smallpox vaccines. The original smallpox vaccines were derived from animals. These often did not meet current good manufacturing practice (GMP) standards, and had rare but significant side effects such as encephalitis. Introduction of modern sterile cell culture techniques led to the development of next generation vaccines such as ACAM2000. ACAM2000 is an attenuated vaccine that is grown in Vero cells. However, ACAM2000 is based on the same seed virus used in earlier generations of vaccines raising concerns regarding its side effect profile. To enhance the safety profile alternative attenuated variants such as Modified Vaccinia Ankara (MVA) and Lister Clone 16m8 (LC16m8) were introduced. Attenuated MVA cannot replicate in most mammalian cells. MVA has been used as a vaccine and a vector in several trials enrolling thousands of individuals including those with HIV infection. MVA has a good safety profile but can be less immunogenic than the replication competent strains such as LC16m8. Developed by the Chiba Serum Institute in Japan, LC16m8 has been safely administered in infants. Certain genetic modifications enabled LC16m8 to maintain its replication capabilities while reducing the risk of reversion of virulence characteristics. Presently, the MVA-BN (manufactured by Bavaria Nordic and known by the tradenames Imvanex, Imvammune and Jynneos) and ACAM2000 vaccines are FDA approved.

Later generations of vaccines became available as smallpox was being eradicated. Randomized efficacy clinical trials were no longer possible. Instead studies with immunogenicity markers supplemented with efficacy data from non-human primates became necessary for regulators to evaluate and compare new vaccines to older generation vaccines. As a result, several questions persist. Is a single dose sufficient or is a booster required? What is the optimal dosing interval for a two-dose regimen? What is the optimal route of administration - subcutaneous or intradermal? How do we design efficacy studies for monkeypox when the disease remains relatively rare? Will the studies need to be different in endemic parts of the world compared to regions such as NY and San Francisco that are experiencing local epidemics? Would a ring vaccination approach as was done for Ebola vaccines be a more suitable in endemic regions? Will the vaccines be effective in interrupting transmission? Are the vaccines suitable for pre-exposure prophylaxis (PrEP) or post exposure prophylaxis and if so what is the optimal timing?

There are many critical questions in vaccinology that need to be addressed but equally important are the socio-behavioral questions that ultimately determine the uptake of all health interventions. What is the community perception of the burden and risk of disease? Is there complacency and if so in which groups? What is needed to build confidence in both pharmaceutical and non-pharmaceutical interventions? What side effects, dosing routes, dosing schedules for vaccines are acceptable to the community? HIV taught us the importance of meaningful community engagement. Key questions such as these can only be addressed through strong and effective collaborations between the affected communities and the scientific community.

It is also important to remember that expertise in infectious diseases is not the sole domain of western academics and public health practitioners many of whom are encountering the disease for the first time. Expertise for this disease lies in the DRC, Cameron, Nigeria and countries where the disease is endemic. African expertise in the diagnosis, clinical management, epidemiology and science of the disease should not be overlooked. Research resources should be directed to scientists from those regions, so that they can contribute to expanding our understanding of the disease. Local scientists can help to unlock the epidemiologic and biologic differences between the different clades of this virus, help guide understanding of transmission dynamics and provide insights from communities that have dealt with this infection for decades. We should use this opportunity to diversify science, end the colonial approach to global health science and level the playing field by working with African scientists as colleagues with empowered voices.

We also should not stigmatize the disease. Although most cases in the current western outbreak are clustered among men who have sex with men, the disease can affect women and children. Transmission can occur in so many ways other than sex. Attitudes to HIV early in the pandemic led to stigma that continues to hang a dark shadow over the fight against HIV. Let us not walk down that path again. Viruses are equal opportunity pathogens and thrive when we are divided.

As we implement medical countermeasures, we should remember that the cost of inequity is high. Inequality in the access to vaccines and therapeutics has been the hallmark of our infectious disease responses to a variety of infections including HIV, Ebola, Covid-19. Several months ago, manufacturers for smallpox vaccines announced supply deals with various high-income countries. The headlines resembled those from two years ago. Our misguided approach then created vaccine nationalism and placed low- and middle-income countries last in line for vaccines. We sowed mistrust and discontent. By each country ‘putting themselves first’ we enable pathogens to spread visa free readily evolving and adapting to humans.

All epidemics show us the importance of communication. As a scientist I love debate. I enjoy having my ideas challenged and I am excited by the breadth of the unknown unknowns in science. In our scientific publications we present data as probabilities with confidence intervals, we express our uncertainties around the data and have peers review and challenge our assumptions. And yet when we communicate to patients and communities, we struggle to communicate uncertainty. Much is unknown about monkeypox today largely because it was a neglected disease of the powerless. Failures in effective communication around monkeypox can lead to harmful behaviors fueled by mistrust as we saw in West Africa during the Ebola epidemic and in the United States during COVID-19. As public health experts we will need to be intentional about how we communicate our certainties and uncertainties about this disease. We need to be willing to say ‘this is what we know today, but it may change as we learn more’. Finding trusted voices to relay key messages is critical. Although difficult in this age of unfiltered media, effective communication and building trust with affected communities will be critical in ensuring the success of our public health interventions.

Recent epidemics from influenza, coronaviruses, Ebola, Zika, HIV have taught us many lessons that we often forget as soon as case counts decrease, or the effects are no longer visible. Novel infectious diseases will continue to emerge and old infections will find new geographies. As humans we must avoid the temptation to forget but instead evolve towards a global collective human response that ensures that we take better care of each other and the environments that we live in.


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