Exclusive: Closure of World’s Only Manufacturing Plant for Monkeypox Vaccine Raises Questions About World’s Ability to Meet Rising Demand
monkeypox
MVA-BN, marketed under the trade name IMVAMUNE, is the world’s only vaccine marketed against Monkeypox.

The manufacturer of the world’s only vaccine approved for monkeypox, Bavarian Nordic, faces a planned closure of its European production plant until late 2022.

With only 16.4 million doses of the MVA-BN vaccine available worldwide, it is unclear how the company plans to meet rising demand for its monkeypox vaccine following the global health emergency of international concern recently declared by the World Health Organisation.

With no new doses expected to leave the facility until early 2023, donations from the few high-income countries that have stockpiled the vaccine, notably the United States, will be crucial to the world’s ability to respond to the outbreak.

Without a new licensing deal to speed up production of their vaccine, Bavarian Nordic risks catalysing a preventable repeat of the inequities seen in the early global response to the Covid pandemic.

Vaccine equity – no better today than before the COVID pandemic?  

Currently, the Danish-based company holds the patent to the only European Medicines Agency and US Food and Drug Agency approved monkeypox vaccine, the technology upon which any vaccination campaign the world might launch to combat the expanding epidemic of cases.  

The lack of clarity, and resulting confusion over the actual state of play in terms of Bavarian Nordic’s own production capacity, and the distribution of available vaccines amongst high-risk countries, is a sharp reminder that the world may be no better prepared today to roll out vaccines rationally and equitably than it was before the COVID pandemic. 

With the rights to the manufacture and distribution of the vaccine solely in Bavarian Nordic’s hands, and more than a dozen countries inquiring about doses, it is the US government that will be in possession of, or contracted to receive, the overwhelming majority of MVA-BN doses due to be delivered in 2022 – roughly adding up to about 14.4 million doses.

The US Defence Department, through the Biomedical Advanced Research and Development Authority (BARDA), financed key elements of the vaccine’s development with contracts amounting to nearly $2 billion between 2003 and 2020, a review of those contracts by Health Policy Watch shows. 

The net result means that, either via donations, or by persuasion of Bavarian Nordic to scale up its production, Washington, once more, could be called upon to take the lead in ensuring equitable access to monkeypox treatments.  That is unless Bavarian Nordic signs new licensing deals with other manufacturers to produce the vaccine.  So far, however, the company’s only recent deals were for the fill-and-finish of 2.5 million doses of already-produced monkeypox, with the US government, along with a recently-announced license deal was with the Chinese firm, Nuance Pharma, to support the development and commercialization in Asia of the company’s MVA-BN® RSV vaccine for prevention of Respiratory Syncytial Virus, which can afflict babies and older people in particular.   

European plant shuttered – production won’t restart until 2023 

Bavarian Nordic’s European vaccine production line, key to its generation of new volumes of the MVA-BN monkeypox vaccine, was closed this spring and will not be reopened until the third quarter of 2022, according to a 9 May investor report. The plant was shuttered prior to the emergence of the global health emergency presented by monkeypox in order to create new production lines for vaccines against rabies and tick-borne encephalitis, Rabipur and Encepur, recently acquired by Bavarian Nordic from GSK.

The investor report states flatly that, “the bulk facility is currently shut down and will not reopen until third quarter of 2022, thus restricting manufacturing capacity in 2022”.

Bavarian Nordic investor report describes the plant closure which aims to diversity its European production lines.

Once re-opened, the company will only begin producing new volumes of the vaccine in early 2023, global health sources in Geneva told Health Policy Watch

Company so far silent on offers to help with  ‘fill and finish’ 

Of the roughly 16 million doses of MVA-BN vaccine said to be available now, most – about 15 million are still in bulk form, according to statements this week by WHO.   

Most of the available 1-1.4 million finished and delivered doses are held in the strategic stockpile of the US, which heavily financed the development of the vaccine, according to the global health forecasting firm Airfinity. 

MVA-BN orders in the US, according data provided by Airfinity.

Virtually all of the 15 million remaining doses, stored in bulk formulation, are already promised to a tiny handful of high-income customers – mostly the United States. 

MVA-BN orders are already promised to high-income countries such as the US, Canada, and the EU.

According to the Airfinity data, as of 20 July 2022, the US had another 13 million doses on order for 2022,  with another 2 million doses spread between Canada, the United Kingdom the European Union, Germany and another “undisclosed European country”. 

Nearly 30 million more doses delivered in earlier years to the US have already expired. 

Company has just one fill-and-finish deal with a US Contractor 

JYNNEOS smallpox vaccine produced by Bavarian Nordic, approved by the FDA for use against monkeypox.

In an exchange with Health Policy Watch, a source at Bavarian Nordic pointed to the recent conclusion of a deal with the US government to fill-and-finish 2.5 million more doses from bulk supplies available, with a US-based firm.

But despite the current closure of the company’s European manufacturing line, there are no current plans to outsource or out-license the bulk manufacturing of MVA-BN, the source indicated.

The company is scaling up production of the MVA-BN vaccine, based on “customer demand” and has “planned our production to satisfy the demand for our vaccine in both the short and the medium term,” the source added, without referring to impacts of the plant closure.  

In a statement hailing the agreement on fill-and finish with the US, Bavarian Nordic CEO Paul Chaplin stated, “expanding our manufacturing capabilities into the United States allows Bavarian Nordic to deliver more monkeypox vaccines to meet the immediate worldwide demand for JYNNEOS”. 

However, without more external licensing agreements, it is unclear how Bavarian Nordic indeed expects to meet increasing demand. 

‘Not enough’ in fill and finish form

Tim Nguyen, Unit Head
High Impact Events Preparedness

Company executives have so far remained silent in the face of offers by the WHO, as well as individual pharma firms, to support more production scale-up, or more rapid “fill-and-finish” of the 15 million vaccines available right now in bulk at a critical point for the global response to the spread of monkeypox. 

Speaking at a press briefing on Wednesday, WHO’s Tim Nguyen noted:

“When it comes to the supply, we know that there is not enough in fill-and-finish form. So the key is what are their [Bavarian Nordic’s] plans for gearing up on fill and finish capacity.”

He added that WHO has already “received offers” from other manufacturers to help the Danish firm to “scale up the fill and finish” – and passed those onto the manufacturer.

South Africa’s Aspen Pharmacare is one such firm that came forward recently with a public offer to support the fill and finish of monkeypox vaccines. 

“At the onset of the COVID-19 pandemic, Aspen was able to swiftly respond by making its extensive sterile formulation, fill and finish capabilities available in response to immediate surging demands”, Aspen said in a press release on Thursday, adding “it would be in a position to step in and replicate this for Monkeypox should global circumstances and demands require this.”

Paradoxically, Aspen’s COVID-19 facility, whose opening was touted last year by WHO officials as a “transformative moment” in the mission to drive down stark vaccine inequalities, is also at risk of closure due to lack of demand for its version of the Johnson & Johnson vaccine “Aspenovax”, which was a flagship product of Africa’s aspirations to localize more vaccine capacity on the continent.  So a contract to fill-and-finish Monkeypox could be a perfect match – if only the suitor was interested. 

Approached by Health Policy Watch, Bavarian Nordic’s spokesperson Thomas Duschek declined to provide further details of the company’s vaccine production and distribution plans – or whether the company would negotiate with Gavi to sell Monkeypox vaccines in bulk for low- and middle-income countries. 

World needs between 180,000 and 10 million doses – WHO  

Speaking at Wednesday’s WHO press briefing, Tim Nguyen, the Unit Chief of the High Impact Events Preparedness divison at the WHO, estimated that the world would need some 180,000-360,000 doses based on an extrapolation of the 18,000 global cases confirmed at the time to immediately begin vaccinating the contacts of those already infected, estimated to be at 10 to 20 people per infected person.

Following Nguyen’s model, the current number of vaccines required would be between 217,550 and 435,550. If a strategy of vaccinating high risk groups was adopted, however, demand would stand at up to 10 million doses, Nguyen said. 

As the vaccine is a two-dose jab, however taking several weeks to take effect, WHO officials have admitted that even if vaccine campaigns were immediately and systematically launched, the burden of the infection will only continue to grow. 

And indeed it already has. From the estimated baseline of 18,000 cases reported by WHO on Wednesday, nearly 21,256 cases had been reported today, according to the WHO’s health emergency dashboard

Monkeypox cases as of 29 July, as reported by Global Health

Meanwhile, according to data from the global research consortium, Global Health, co-sponsored by Harvard and Oxford University, the caseload of confirmed and suspected cases totals 23,454 cases across 77 countries. 

Another COVID replay: WHO and Gavi urge rich countries to donate vaccines

While vaccine demands are spread among those countries now reporting cases, only a handful of nations, and primarily the United States, hold the keys to available supplies that could be used right away to stem the pandemic tide.  

This has left the WHO and its associates asking for vaccine donations, another striking replay of the early days of the COVID vaccine rollout. 

“We urge countries with stockpiles – or supplies on order – to be generous and flexible in releasing doses to countries with cases that do not have access to ensure equality,”  a spokesperson for the Vaccine Alliance (GAVI) told Health Policy Watch. 

HO’s Chief Scientist, Soumya Swaminathan also speaking at last Wednesday’s WHO briefing, echoed that, saying: “we are in discussions with the manufacturers to get an idea of availability of doses. Many of them have already been committed to countries, so we would like to explore the possibility of a donation from countries that do have doses, to put them in a stockpile.”

But the United States also announced last week that it will begin deploying some 800,000 doses of its available MVA-BN stock to vaccinate at risk groups at home.  That leaves little in its strategic stockpile for donations – until at least the 2.5 million doses of fill-and-finish are delivered.  

Asked for more details about the WHO’s “discussions” with the pharma firm, a WHO spokesperson suggested that Health Policy Watch, “speak to Bavarian Nordic.”

Replay of COVID Vaccine playbook?  Global health officials tread carefully  

Gavi’s CEO Seth Berkley

Despite the emerging tensions between vaccine demand and supply, leading global health officials have so far tread gently in their comments about the Danish vaccine company, perhaps due to the world’s dependence on this single company’s policies to get the pandemic under control.

“I look at Bavarian Nordic, and it’s a good company,” GAVI CEO Seth Berkley noted in a press briefing Thursday. 

But, he added, Bavarian Nordic “doesn’t have a large fill finish production facility, so it may be that if four doses are needed, then moving towards a fill and finishing approach as Aspen or the few other manufacturers have offered would be a way to move forward”. 

Anne Simon, Unit Chief of the EU’s Health Emergency and Preparedness Response Authority (HERA), told Health Policy Watch, “the European Commission, notably through HERA and the European Medicines Agency, stand ready to support Bavarian Nordic to scale up vaccine production as is needed”.

The Global Fund was more blunt: “The global COVID-19 response demonstrated structural global health inequities which left low and middle-income countries exposed to harmful vaccine nationalism”, a spokesperson for the Global Fund told Health Policy Watch, “we must acknowledge the very real global double standards, and we must strive to do better”. 

Other Vaccines: Unsuitable or Unavailable

The smallpox vaccine supply is still limited and concentrated in only a few countries.

In theory, there are two other vaccines available against smallpox – and thus potentially effective against monkeypox. But neither are licensed for monkeypox as such. 

First is the LC16, manufactured by Japanese pharmaceutical KM Biologics, the only second or third-generation smallpox vaccine to be licensed for use in children by the WHO. Officials at the WHO, however, have noted that Japan views the vaccine as a national asset, and the country has no plans to share its stockpiles. 

When KM Biologics was asked about plans for production scaling and prospects of working with WHO or GAVI to provide vaccines for distribution in low and middle-income countries, the company told Health Policy Watch: “we are afraid we cannot be of help in the matters described in your email”. 

The world also possesses around 100 million doses of the older generation ACAM2000 vaccine that contributed to the eradication of smallpox, but experts deem the risk of adverse effects too high to deploy unless absolutely necessary.

“The available vaccines are not routinely used because of the risk of adverse events”, notes the New England Journal of Medicine in a 2018 study, “they would not be used in the general population unless Variola Virus (VARV) exposure were either known or suspected”.  

“This is a global challenge”, GAVI CEO Seth Berkley explained at a press conference on Thursday, “if you have rare diseases, or small producers for disease, there’s not enough attraction to have them produced by many different manufacturers”. 

‘Threats Anywhere Can Become Threats Everywhere’

US signs launched mass vaccination of at-risk groups with 800,000 doses of its available stock of monkeypox vaccine

“The unanticipated emergence of monkeypox outside of Africa is a perfect case study of how threats anywhere can become threats everywhere”, Oxford Professor of Emerging Infections and Global Health Peter Hornby said on behalf of the European Clinical Research Alliance for Infectious Diseases in a press release responding to the monkeypox outbreak, “it exemplifies the need to work as a global community to identify and counter all infectious disease problems, wherever they occur, and whomever they affect”.  

“It is frustrating to see the same pattern repeating itself again”, Oxford Professor Piero Olliaro and Emmanuel Nakoune of Institut Pasteur,  leaders of a key study in the Central African Republic on the efficacy of antiviral agent tecovirimat in treating monkeypox, wrote in the British Medical Journal during the early stages of the high-income country outbreak.

“Attention is only paid when certain diseases hit high-income countries, exemplifying our collective failure to properly address “epidemic preparedness” and “global health,” though they are nominally on top of our agenda with the COVID-19 pandemic”. 

Paradoxically, while the MVA-BN vaccine is registered in Europe, where the recent monkeypox outbreak first became apparent and the heaviest burden has now occurred, it is not even registered in the 9 to 12 central and West African countries where the disease is endemic. 

Several thousand suspected cases have been reported by WHO in front-line countries where monkeypox is endemic this year, including cases of the deadlier Monkeypox Clade 1, that circulates in central Africa, and has a 10% mortality rate. To date, no deaths have been reported from the variant affecting high-income countries.

This lack of regulatory approval can also create barriers to access, even if supplies are adequate, Oxford professor and former senior WHO official Piero Olliaro explained in an interview with Health Policy Watch

“There are huge asymmetries: both treatments and vaccines are registered in high-income countries, but not in endemic low-income countries,” said Olliaro, “Ebola medicines are in exactly the same situation, with two drugs registered in the US for treating Ebola, but not registered or available in the endemic countries, not even in the Democratic Republic of Congo where the studies were done”. 

But this is just one issue among a whole spectrum of public health and health system challenges that are faced in rolling out new vaccines or drugs.

Fixing the market failure – but not the public health failure 

On supply issues, a series of public sector incentives have succeeded in stimulating R&D in some historically neglected diseases, including SARS-COV2, Ebola and Monkeypox, Olliaro notes.  

“Essentially, there are pull and push mechanisms in place, which have been set up and have succeeded in fixing the market failure, at least for some diseases,” he said. 

“The whole market for neglected diseases suffers, by default, from market failure,” Olliaro explained, “massive packages of incentives to develop certain products, including the subsidizing and de-risking of development for pharmaceuticals dealing with these niche diseases.

The mechanism referred to by Olliaro is the US Government’s Priority Review Voucher programme, a sort of pharma ‘prize’ that` allows the developer  of a new drug or vaccine for qualifying “tropical diseases” to obtain more rapid FDA review of another upcoming product, or to trade off the voucher to another firm for their use on an upcoming drug, earning benefits of millions or tens of millions of dollars.

“These mechanisms fix the market failure, but they do not fix the public health failure, which is the availability of these drugs in the countries where these diseases are endemic,” Olliaro explained, adding, “this system has been developed to deal with a rich country problem.”

“Like for COVID, through a combination of having a single producer monopoly, suddenly increasing demand, and hoarding, then if we need vaccines in Africa or any other low and middle income countries, there is none, unless someone is prepared to donate.” 

R&D Contracts of Bavarian Nordic by the US

Since 2003, the total value of R&D contracts awarded to Bavarian Nordic by the United States government sits north of 1.9 billion USD, according to US public records.

And yet, the world still faces a shortage of this same vaccine.

Part one of a Health Policy Watch series on global monkeypox preparedness. 

updated on 1 August 2022 with correction in description of Bavarian Nordic’s MVA-BN® RSV vaccine as a candidate for prevention of respiratory syncytial virus. 

Image Credits: FIH Partners , Bavarian Nordic, Barda , Global Health , The Hill/Twitter , USA Spending .

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