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Monkeypox vaccine shortage – Can this be solved by mRNA vaccines ?

What lessons can be learned by Africa and its global partners as the continent expands vaccine manufacturing?

As monkeypox vaccination stations opened up in major cities like New York and San Francisco we are reminded that monkeypox vaccines are not readily available in parts of Africa that have been dealing with monkeypox for years. Monkeypox vaccines are in short supply, manufacturing takes time, and a question I am often asked is why we can’t just make an mRNA vaccine and roll out supplies rapidly?

The successful and rapid development of the coronavirus vaccine against SARS CoV2, has boosted our confidence in humankinds’ ability to fight against new and emerging pathogens. Unfortunately, not all pathogens are the same, they have significant differences in their genetic makeup, how our human immune system responds to them and the nature and severity of the disease that they cause.

The monkeypox virus is an orthopoxvirus. It belongs to the same family as the smallpox, cowpox, vaccinia and ectromelia viruses. The virus was first described in monkeys in Europe. Although it is called monkeypox the rodent is the natural host and transmits the virus to humans and other animals. The immune response generated against one related member of the orthopox virus family affords protection against other members of the virus family. Although smallpox vaccination is often attributed to Edward Jenner, many societies before him had started to inoculate people with small doses of smallpox to prevent more severe infection. English country doctors including John Fewster, provided this technique as a service. To avoid devastating disease with a high mortality, he would inoculate a patient with a small dose of smallpox and provide room and board and care for a mild case of the disease. Using the same technique on local farmers, he noted that some of them didn’t develop a scar after inoculation. It seemed as though they were already immune to smallpox. As he wondered what made them different from his other patients one of the farmers mentioned that he had had cowpox suggesting that cowpox infection may also lead to protection against smallpox. Years later Jenner built on this observation to develop his cowpox-based smallpox vaccine (he inoculated a boy with fluid taken from a milkmaid’s lesion). This cross-protective response is what is used today for the monkeypox vaccine. Vaccines developed for smallpox are used to protect against monkeypox.

Our smallpox and monkeypox vaccines are based on 18th century knowledge. Are we able to bring this into the modern era, be more targeted, simplify manufacturing and rapidly increase supply? The monkeypox virus uses DNA for its genetic code and has a large genome that is a little over 6 times the size of that of SARS CoV2 an RNA virus. The monkey pox virus encodes more than 200 proteins. A protective immune response to smallpox is complex and made up of responses against a broad array of surface proteins against the two virus forms – the mature virion and enveloped virions. In addition, viral entry into host cells is mediated by several viral transmembrane proteins that attach to various human host proteins. In contrast, SARS CoV2 spike protein binds to a single dominant human receptor and antibodies generated against it stimulate a robust immune response that blocks viral entry. As a result, we were able to rapidly produce effective vaccines. To date the WHO has approved at least 15 SARS CoV2 vaccines across multiple different platforms including mRNA vaccines, protein subunit vaccines, viral vector vaccines and inactivated vaccines. An effective immune response against orthopox viruses is a result of complex combination of antibody and T cell responses against multiple viral proteins, isolating one or a couple of dominant monkeypox proteins to be expressed by mRNA or a viral vector may not be effective.

The live vaccines used for smallpox and monkeypox are grown in cell culture systems. The current vaccine in use in the United States is grown in chicken embryo fibroblast cells in a complex manufacturing process that takes a while to ramp up. As a consequence, the US is beginning roll out using vaccines that it has available from its strategic stockpile as it waits for more vaccines to be manufactured and become available. Most African countries don’t hold pandemic or bioterrorism ready strategic stockpiles of vaccines, medications, or PPE. Its hard to plan for a rainy day when failing to adequately meet current health needs.

The mRNA revolution has been phenomenal and has helped much of the world resume life and economic activity despite the ongoing COVID-19 pandemic. The mRNA vaccines are manufactured in cell free systems and provide some distinct advantages to other vaccine manufacturing techniques. However, their use in infectious disease vaccines is probably best suited for infectious disease where protective immunity is a result of focused immune response to one or a few targeted proteins. Infections where we do not fully understand the correlates of immunity or those that require a complex interplay between T and B cell responses against multiple proteins may be challenging for mRNA or some viral vectored vaccines.

The COVID-19 pandemic and lack of vaccine access for monkeypox has exposed weaknesses in Africa’s vaccine manufacturing capability. Africa has the fastest growing population in the world, and has a huge demand for childhood vaccines. Africa consumes 30% of global vaccines, but the total value of Africa’s consumption is less than 6% of the global vaccine market, and the continent manufactures <1% of its own vaccines. The challenges faced by COVAX as it tried to provide rapid access to vaccines in Africa, has put a spotlight on the lack of manufacturing facilities in Africa. Ongoing infectious disease crises such as COVID-19, monkeypox, polio and HIV highlight the need for Africa to build vaccine manufacturing capability. However, this is a complex challenge on a continent with weak research and development infrastructure, fragmented markets, and complex procurement making the sustained investments in manufacturing a challenge.

There are currently several manufacturing initiatives across at least 13 different countries on the continent. This may be too broad and not sufficiently focused for a population of 1.2 billion where the return on investment may take decades to realize. Many of the initiatives are focused on mRNA vaccines, some include protein subunit vaccines, inactivated vaccines and viral vectors. Africa currently has some capability to manufacture live attenuated vaccines in human and animal health. Strengthening the capacity and technical skills in this area will be critical in expanding our ability to manufacture other live attenuated vaccines such as those for polio, smallpox, measles etc. Although the manufacturing processes for one type of vaccine are not interchangeable with that of another type, building the ecosystem to support manufacturing and the technical capability across platforms is critical. As Africa considers expanding capability in vaccine manufacturing let us remember that the pathogens that cause human disease are incredibly diverse. The diversity is reflected in the genomic material, how easily the pathogen mutates, its transmission efficiency and the correlates of immunity. If the African continent is to become self-sufficient in vaccine manufacturing for SARS CoV2, measles, monkeypox or other vaccines we need to have a diversified platform approach. A unified continent-wide approach is needed. Generating expertise to support the manufacture of routine vaccines for the continent's growing population, emerging infections and the Africa specific infectious diseases is crucial. The whole world should rally together to a smart expansion of manufacturing capacity in Africa as an uncontrolled infectious disease somewhere is an infectious disease everywhere.

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