How easy would it be to make a pandemic flu vaccine against H5N1

The ongoing spread of H5N1 bird flu to mammals and evidence of transmission between cattle herds in the US is generating global concern, with senior World Health Organization (WHO) officials urging vigilance for any new mutations that could pose a threat to humans.

While there is no sign of such changes yet, scientists are working to ensure that vaccine production could ramp up quickly in the event of a human influenza pandemic. But how long would it take to create such vaccines, and what would the process entail?

Even though the current risk to humans from H5N1 and other current animal influenza viruses remains low, efforts are already underway to develop pre-pandemic preparedness vaccines against them.

Ongoing surveillance

The WHO's global influenza surveillance and response system (GISRS) is a global network of laboratories operating in 129 WHO member states that collect and analyse respiratory virus specimens from sentinel surveillance sites, such as doctors' surgeries and hospitals, to gain an impression of which influenza viruses are circulating. They also send representative samples of these specimens to one of seven regional WHO collaborating centres for further analysis, with the results helping to inform which viruses go into the seasonal influenza vaccines each year.

These efforts are further strengthened by WHO's Pandemic Influenza Preparedness (PIP) Framework - a system through which countries will be provided with access to pandemic doses of influenza vaccine and strongly encouraged to share virus samples.

Alongside these human surveillance efforts is a network of experts in animal influenza known as OFFLU, who analyse virus specimens from birds, pigs and other animals to better understand which viruses are circulating in these creatures and how they are changing. These results are also shared with WHO to help inform the composition of flu vaccines and assess risks.

So far, these surveillance efforts suggest that H5N1 bird flu remains predominantly an animal health issue for now, and while reports of it spreading between US cattle may sound alarming, "we have seen that before with mammals [such as mink], where you get animal-to-animal spread, and still it doesn't seem to come across into the human population," said Dr Ruth Harvey, deputy director of the Worldwide Influenza Centre at The Crick Institute in London, a WHO collaborating centre.

Those human infections that have occurred have been in people with job-related or recreational exposures to birds or infected mammals, and there is no evidence of human-to-human transmission.

"Signals that could raise the public health risk include multiple, simultaneous reports of human infections with A(H5N1) viruses following exposure to birds or other animals, or identification of spread from one infected person to another," the US Centers for Disease Control and Prevention (CDC) said.

Candidate virus library

Even though the current risk to humans from H5N1 and other current animal influenza viruses remains low, efforts are already underway to develop pre-pandemic preparedness vaccines against them. The 'candidate vaccine virus' strains in such vaccines are recommended by WHO and attenuated so they cannot cause disease. They could be used by vaccine manufacturers to produce a flu vaccine if it were needed.

"If there is a new virus emerging in birds or domestic mammals that isn't similar to any previously recommended candidate vaccine viruses, or if there is a human case of influenza that has spilt over from animals, WHO will recommend that a new candidate vaccine virus is made for that virus," said Harvey.

This means that as soon as WHO scientists at the Collaborating Centres can get hold of samples of a new animal influenza virus - for example, the virus that's causing the current outbreak in US cattle - they will test to see if antibodies from animals that have been immunised using a vaccine made from an existing candidate vaccine virus will recognise this new strain. If they don't, WHO will create a new one, by combining the virus with a laboratory-adapted influenza strain that has been attenuated so it cannot infect humans or cause disease, but grows very well in eggs, as that is what manufacturers use to produce flu vaccine.

"What you are ultimately creating is a virus that can be grown in eggs very safely, because it is incapable of infecting humans, but it has the surface proteins of the new virus. This is what would be included in the vaccine," Harvey said. "These candidate vaccine viruses are then provided free of charge to anywhere in the world that wants to use them, to produce a vaccine."

Production scale-up

WHO has been making these candidate vaccine viruses for non-seasonal influenza viruses that circulate in animals since the late 1990s, while the egg-based manufacturing process that would largely be used to scale up production has been in use for more than 70 years. This means that the safety profile of this type of influenza vaccine is well-established.

Existing production facilities for seasonal flu vaccines could also be switched over to produce pandemic flu vaccines - which are easier to manufacture as they only have one candidate virus - with first doses potentially becoming available between four and six months after the declaration of a pandemic, and a best-case annual production capacity of around 8.31 billion doses.

Impressive as this figure is, because so few people have been exposed to H5N1, it is likely that two doses of vaccine would be required to trigger an adequate immune response, so even under the best-case scenario there would only be enough vaccine to cover around half of the world's population during the first year of production.

Vaccine equity

In reality, production capacity is likely to be even lower: assuming a moderate-case scenario, researchers have estimated that 4.15 billion doses could be produced per year - but even this depends on there being enough chicken eggs, fill-and-finish facilities, and other supplies including adjuvants to make the vaccines.
Also, while efforts to expand manufacturing capacity to low-and middle-income countries are ongoing, most flu vaccine manufacturers are currently located in high- or upper-middle income countries.

"This obviously leads to a lot of challenges and concerns, both about speed and about equity," said Dr Nicole Lurie, executive director for emergency preparedness and response at the Coalition for Epidemic Preparedness Innovations (CEPI). "Scarcity is the enemy of equity. Existing techniques for making flu vaccine work really well, but they are slow. And if you make vaccines slowly, that gets you to scarcity pretty quickly."

The good news is that the COVID-19 experience may have provided the means to make additional vaccine doses, and to do so faster, through newer technologies such as mRNA-based vaccines and other approaches.

Several such influenza vaccines are currently in late-stage clinical trials, and the hope is that by the time the next flu pandemic hits, they will have advanced even further.

Because these candidates are not licensed vaccines, the regulatory pathway for them would need to be worked through and clarified before they could be mobilised in the event of a pandemic. However, "they do offer something interesting in terms of enabling a much more rapid response than traditional egg-based vaccines, and their supply has not already been bought up through contingent purchase agreements," said Freya Hopper, a senior strategy manager at CEPI.

Immunisation infrastructure

Another positive legacy of the COVID-19 pandemic is that the delivery systems and processes to deliver vaccines into people's arms are stronger than they were pre-pandemic. "Every country in the world has adult vaccine programmes or has at least delivered vaccines to adult populations because of COVID, and the same adult populations - health workers, pregnant women, elderly people - are likely to be vulnerable during an influenza pandemic," said Dr Joseph Bresee, an epidemiologist and director of respiratory virus prevention programmes at the Taskforce for Global Health, an international non-profit organisation based in Decatur, US.

"The challenge is that those programmes will degrade over time if they are not maintained or provided with the resources to be strengthened. That could be a problem because those programmes take at least as long as new vaccines to be developed."

Strengthening existing seasonal flu vaccine programmes could be a good place to start, Bresee added. "Evidence from the COVID vaccine response is showing that the presence of an influenza vaccination programme in place before the pandemic, resulted in faster vaccine deployment of COVID vaccines and higher coverage of at-risk groups than in countries without influenza vaccination programmes.

"As a result, we have been working with countries to establish or strengthen their influenza vaccination programmes as a pandemic readiness tool."

Willingness to be vaccinated

Even if there are enough doses, a final obstacle will be persuading people of the benefits of getting vaccinated. "Here, we're probably in a less positive place than we were before COVID-19, where there's more hesitancy, more suspicion of vaccines and probably less willingness to be vaccinated in many quarters of the population in every country," Bresee said. "Tackling this issue will require lots of resources, lots of tailored strategies for different people, lots of complexity, but obviously it cannot be ignored."

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