We've never seen anything like it. Covid-19 only emerged in December 2019, but within months, the race for a vaccine already involved 150 candidates and by November 2020, two vaccines had reported back, showing around 90 per cent efficacy against the virus. The World Health Organization (WHO) plans to vaccinate two billion people by the end of this year (2021). Effective Covid-19 vaccines are crucial if millions of lives are to be saved and economies given a chance to recover.
These Herculean and fast-paced efforts contrast with the painstaking 30 years it took to develop an effective polio vaccine or the ten years to combat measles. A cynic might be forgiven for asking whether so much attention would have been paid to Covid-19 if it wasn’t so easily transmitted and had travelled no further than China, rather than landing on the doorstep of Western nations.
The same cynic might also politely enquire as to when such urgency will be devoted to the group of hideous illnesses that are collectively, and without irony, described as ‘neglected diseases’. A diverse group of communicable horrors, neglected diseases prevail in tropical and subtropical regions in 149 countries, affect more than one billion people and cost developing economies billions of dollars every year. The WHO classifies 18 diseases in this way.
‘The situation we see with diseases that are the scourge of humanity, such as leishmaniasis or sleeping sickness, isn’t comparable with Covid-19,’ says Marie-Paule Kieny, head of the board of directors of the Drugs for Neglected Diseases initiative (DNDi), a non-profit research and development organisation. ‘History tells us it’s difficult to harness the same leverage for accelerating resources. This is not something that happens with “routine” situations. What really generates goodwill and change is a sense of a crisis.’
According to the DNDi, of the 1,556 new drugs approved between 1975 and 2004, only 21 (1.3 per cent) were specifically developed for tropical diseases and tuberculosis, even though these diseases account for 11.4 per cent of the global disease burden. ‘The old diseases, such as leishmaniasis, will not attract more funding – they are centred in particular areas, they don’t really move around the world,’ says Mohga Kamal-Yanni, a consultant on global health and universal access to medicines. ‘These are diseases “over there somewhere” that we’ve judged will not affect us in the West. The only way it changes is if a disease jumps country. The political importance of a disease is usually translated into funding for that disease.’
The global reactions to Ebola in 2014 and SARS-CoV-1 in 2003 illustrate this. ‘There was huge panic – the world was turned upside down,’ says Kamal-Yanni. ‘But once everyone realised that SARS was not going to infect the world, interest was lost in developing a vaccine. The same happened with the Zika virus [in 2015], which flared up and made everyone worried.
But it calmed down, so the West has deemed it not to be a threat to us – but it’s a horrible disease.’
Another concern is that long-term research into vaccines for diseases that have a grinding effect on the developing world also get sidelined during times such as these. ‘Covid-19 had an immediate effect in that people who were working on other vaccine work had to stop because of lockdown,’ says Kamal-Yanni. ‘Then they were told they had to drop everything, put research on the backburner and work on Covid instead because that’s where the funding was being diverted to.’
Diseases such as Chagas – which affects seven million people ever year – were already neglected before the pandemic; now, the diversion of resources to fight the pandemic, strains on healthcare facilities and patient concerns about contracting Covid-19 when visiting clinics, all put pressure on those suffering, or dealing with Chagas and other neglected diseases. Such trends create ethical and medical implications: many neglected diseases amount to co-morbidities that make people vulnerable to Covid-19. Chagas, for example, causes cardiac, gastrointestinal and other complications that could increase susceptibility to Covid-19.
The Neglected Diseases: Part 1
• Dengue: A mosquito-borne infection causing a flu-like illness that may develop into severe dengue and cause lethal complications. A partially effective vaccine became available in 2016 but there are no anti-viral therapies.
• Rabies: Transmitted to humans through the bites of infected dogs, it’s invariably fatal once symptoms develop. Each year, 15 million people are vaccinated against rabies.
• Trachoma: Infection transmitted through direct contact with eye or nasal discharge. Left untreated, it causes irreversible corneal opacities and blindness. Up to 80 million people are infected every year but can be treated with antibiotics and improved hygiene.
• Buruli ulcer: A debilitating mycobacterial skin infection causing destruction of the skin, bone and soft tissue. Affects 80,000 people a year. Treatment comprises a combination of antibiotics and complementary treatments.
• Yaws: A chronic bacterial infection that affects skin and bone. Primarily affects children in tropical forested areas. There is no vaccine.
• Leprosy: A complex disease caused by infection mainly of the skin, peripheral nerves, mucosa of the upper respiratory tract and eyes. Leprosy is curable with a combination of drugs. The number of people with leprosy has dropped from more than five million over the past 40 years to around 200,000.
• Chagas disease: A life-threatening illness transmitted through contact with insects, ingestion of contaminated food, infected blood transfusions and congenital transmission. Chagas can be treated with two antiparasitic medicines that are nearly 100 per cent effective.
• Human African trypanosomiasis (sleeping sickness): A parasitic infection spread by the bites of tsetse flies. Almost 100 per cent fatal without rapid diagnosis and treatment. Six medicines are donated by their manufacturers.
• Leishmaniases: Transmitted through the bites of infected female sandflies. In its most severe (visceral) form, attacks the internal organs and in its most prevalent (cutaneous) form, causes face ulcers, disfiguring scars and disability. Treatment can’t provide a sterile cure and the parasite can cause a relapse.
• Taeniasis and neurocysticercosis: Caused by adult tapeworms in human intestines. Leads to cysts in the brain and tissues, and seizures. The WHO says that improved, rapid diagnostic tools are still needed.
Covid-19 has unquestionably seen funds diverted. The WHO says that doctors and health workers across Asia and southern Africa have had to reassign budgets and equipment to track Covid-19 infections rather than TB. Excess deaths from TB, which kills around 1.4 million people in a typical year, may turn out to be as high as 400,000 in 2020, according to the WHO (bedaquiline, the first TB drug for 40 years, was only approved in 2012). The same concerns apply to the roll-out of a Covid-19 vaccine. Hayley MacGregor, a research fellow at the Institute of Development Studies at the University of Sussex, points out that people charged with delivering the vaccine are likely to also be responsible for administering the MMR vaccine to young children. ‘It will require a bit of effort to strengthen systems to do both,’ she says.
The choice of where investment goes has also appeared to be binary at times, MacGregor adds. ‘The question has been which diseases get prioritised and which get neglected. An obvious response is required to a disease, such as Covid-19, that has a high mortality – but is that at the expense of diseases with high morbidity? Covid-19 has forced that debate, but it shouldn’t be a question of either/or.’
More positively, the mobilisation in response to Covid-19 could improve the ways in which vaccines for less-heralded diseases eventually see the light of day. ‘When you have such an unprecedented event, you get paradigm shifts on how things can be done, especially in relation to the sheer speed of biomedical research,’ says Andy Powrie-Smith, communications director at the European Federation of Pharmaceutical Industries and Associations.
The lessons learnt include an understanding of how improved data-analysis technology can accelerate trials. Increased speed of regulatory approval and an ability to develop vaccines at scale could also be here to stay, suggests Powrie-Smith. ‘Rather than wait for the end of the entire process, you can have a more dynamic approach to presenting data. The regulatory rigour takes place as you move along the process, and that doesn’t involve cutting corners.’
One of the most striking aspects of the Covid-19 research is the unprecedented alliance of public, private, academic and philanthropic sectors it has triggered. ‘Coalitions are not new, but the effort and funding have been to a different degree than with diseases such as dengue or the stuttering investment in the Zika virus,’ says MacGregor. This is typified by the partnership between Pfizer and BioNTech that saw the first vaccine candidate over the line. The former is a pharmaceutical giant, the latter a medium-sized enterprise that received US$400 million from the German government. The Oxford Jenner Institute’s collaboration with Astrazeneca follows a similar model. ‘Covid has seen hitherto unseen levels of collaboration.
Look at the frontrunners for the vaccine – they are all smaller organisations or companies coupled with a larger player,’ says Powrie-Smith. ‘The sum has been greater than the parts. Many people think Covid-19 research has only emerged in the past six months, but it is based on years of work.’
As Kamal-Yanni points out: ‘The Oxford Covid vaccine didn’t happen out of the blue; they had material and research drawn from years of work on SARS-1. The donkey work is done over the years before.’
The speeding up of data processing and trials may also incentivise pharmaceutical companies to back a wider range of vaccine research, says Powrie-Smith. ‘Commercial arguments about the length of a process are something companies have to consider as part of their plans. Regulatory bodies such as the EMA in the EU and the FDA in the USA can take advantage of this.’
The sharing of information also offers lessons for the future, suggests Manuel Martin, medical innovation and access policy advisor at Médecins Sans Frontières (MSF). ‘China shared the Covid-19 genome very early on, which was extremely useful – but then companies all went off into their own silos,’ he says. ‘The question is whether companies that come up with Covid-19 and other vaccines are prepared to share how to produce their vaccine. So far, we haven’t seen that.’
FLAWS IN THE SYSTEM
There are others, however, who feel that a more fundamental shift is required and that the business model that determines which vaccines get the green light for research and – above all – development (or manufacture and scaling up) has to be fundamentally reshaped. This is because of a simple reality: most vaccines are manufactured by private companies. Generally, research for vaccines is funded by public money, through either universities or public institutions such as the US National Institutes for Health. These are then picked up by pharmaceutical companies that make a judgement – to put it bluntly, they cherry-pick – on which medicines to develop and scale up.
‘What we have really learned from Covid-19 is that the number-one element is the importance of public money,’ says Kamal-Yanni. ‘Vaccine development usually takes years and that’s mainly because researchers have to apply for grants and argue the case with donors. With Covid, money poured into R&D. The problem I have is how pharma companies that produce vaccines present themselves as saviours of the world, when it’s actually public money that supports the research. The companies then sell it back to us, so the public pays twice, which is outrageous.’
Kieny suggests that the funding models for Covid-19 vaccine research highlight the fact ‘that most states have given up their sovereignty over R&D and passed it to the private sector. Governments are short-lived, saving money is what they want to do, their people move on. Research in pharmaceuticals is long term. This means that public laboratories that do the research will then try to negotiate their innovation to private companies to do the development side.’
So will this prevailing model, which has traditionally driven the development of vaccines, leave hundreds of millions of people squeezed out of Covid-19 vaccine programmes? It seems that those lower-income nations, unable to pay the prices asked by vaccine producers, will be reliant on philanthropic organisations or purpose-built entities as COVAX, which was set up by the WHO, GAVI (an initiative that also includes UNICEF, the World Bank and the Bill & Melinda Gates Foundation) and the Coalition for Epidemic Preparedness Innovations. COVAX is both funding R&D and negotiating pricing to ensure access for the poorest nations. ‘With Covid, it looks like the COVAX programme will be required to fill in the gaps and make sure poorer nations get the vaccine, but it shouldn’t be like that,’ says Kamal-Yanni.
It appears that there will be huge variations in what is defined as ‘equitable distribution’. Unsurprisingly, the West will be first in line for the jab. GAVI declined to be interviewed for this article but acknowledges on its website that, ‘subject to funding availability, funded countries will receive enough doses to vaccinate up to 20 per cent of their population in the longer term. In the West, the proportion who are vaccinated is expected to be much higher, around 50 per cent.’
Martin describes this attitude as ‘post-colonial’ and adds: ‘The idea seems to be, “You can have some of the vaccine, but only after we’ve made sure all our people have got it.” That needs to change.’
Yet, the only way to ensure the equitable distribution of a vaccine, says Kamal-Yanni, is to establish a system of open licences. ‘A pandemic is not the time for people to need to make a profit for the demand to be met,’ she says. ‘It has to be a people’s vaccine. There is a moral argument for it being free at the point of use and that should be primary. That’s also a practical argument because if you really want to stop Covid in its tracks, you have to protect everyone.
The neglected diseases: Part 2
• Dracunculiasis (guinea-worm disease): A nematode infection transmitted by drinking-water contaminated with parasite-infected water fleas. No drug treatment is available.
• Echinococcosis: Infection caused by the larval stages of tapeworms, which form pathogenic cysts in humans. Transmitted by ingestion of eggs, most commonly shed in the faeces of dogs and wild animals. Expensive, complicated treatment includes surgery and/or prolonged drug therapy.
• Foodborne trematodiases: Infection acquired by consuming fish, vegetables and crustaceans contaminated with larval parasites. Treatment can be offered through preventive chemotherapy.
• Lymphatic filariasis (Elephantiasis): Infection transmitted by mosquitoes that causes abnormal enlargement of limbs and genitals. Available medicines have limited effect.
• Onchocerciasis (river blindness): Infection transmitted by the bite of infected blackflies. Can lead to blindness. Medicine needed at least once yearly for up to 15 years.
• Schistosomiasis (Bilharzia): Trematode infection transmitted when larval forms released by freshwater snails penetrate human skin. Treatment with Praziquantel is effective, safe and low-cost.
• Soil-transmitted helminthiases: Nematode infection transmitted through soil contaminated by human faeces causing anaemia, vitamin A deficiency, and stunted growth. WHO-recommended medicines are effective, inexpensive and easy to administer.
• Mycetoma: a chronic inflammatory skin disease which usually affects the lower limbs. Infection is thought to be caused by fungi or bacteria from thorn pricks. Treatment involves a long-term antibiotics or antifungal combination but has many side effects, is expensive and rarely available.
• Chromoblastomycosis and other deep mycoses, scabies and other ectoparasites: Globally estimated to affect more than 200 million people at any time. Treatment involves application of a topical scabicide.
‘The producer of a vaccine can name the price a country has to pay for that vaccine,’ she continues. ‘Countries such as India, Brazil, South Africa will be able to pay for it, but what about Sierra Leone or Mauritania?’
One way to change this model would be for nation states to discover an enthusiasm for both research and development. Kieny sees merit in the EU establishing a production company to develop drugs for everything from front-line cancer treatment to neglected diseases. ‘There is no doubt the state should be more invested in health for their own citizens,’ she says. ‘It would be self-serving because you are helping people at home as well as abroad. We need to invest public money into the development of innovations made by the public sector and small biotech companies in order to ensure that the right treatments will be available at an affordable price. The realisation of a need for state investment may see a ripple effect in drugs for neglected diseases, but whether that translates into real progress, we will have to wait and see.’
This approach could usefully apply to the continent of Africa, too. ‘Southern [nation] governments have to realise the importance of investing in R&D for vaccines,’ says Kamal-Yanni. ‘Otherwise, as with Covid, they will be waiting for the North to realise that a disease might affect them, too, before they take it seriously. The North will develop a vaccine and name the price the South will have to pay to access it.’
MSF feels this is an important point. ‘The ideal situation is that African R&D comes up with vaccines and production for diseases such as Ebola, not the West,’ agrees Martin. ‘There are research hubs in Africa – Senegal has some diagnostics capability [the Pasteur Institute in Dakar] but it is still in its infancy. It will take time and a willingness on the part of the international community.’
Kieny reports that attempts to create such a system have generally foundered across the continent. ‘The scientific knowledge and expertise to set up something like this exists, so there’s a valid argument for doing it. However, one of the main issues is governance – which applies elsewhere, not just in Africa. Who will put money in? If nobody regulates [the drugs produced] – no-one will buy and manufacture them. If you run these through charities or donors, then the money only goes so far. If the state will not invest, then everything just collapses.’
Martin also feels that a more equitable model is necessary and that this should reflect everything from access to vaccines to transparency and cost. The sheer scale of voluntary action and public-spirited goodwill should also be taken into account, he says, pointing to the large number of citizens who offer to participate in trials for free and do so in the knowledge that if they are in the placebo half of a trial, their lives may be at risk. ‘I understand pharmaceutical companies need to make a profit, but the question is whether their expectations go well beyond what could be considered reasonable,’ he says. ‘Clinical trials are expensive, which is why pharmaceutical companies are wary of conducting them. But so much public money and effort goes into the practicalities of rolling them out. That should mean greater transparency when it comes to what prices are paid, as well as a greater sharing of know-how.’
What’s clear is how investment in vaccines saves money in the long term. Johns Hopkins University in Baltimore reports that for every US$1 spent on immunisation, US$21 are saved in health-care costs, lost wages and lost productivity due to illness and death. When considering the value people place on lives saved by vaccines – which is likely to include the value of costs averted as well as the broader societal value of lives saved and people living longer and healthier lives – the estimated return on investment rises to US$54 per US$1 spent.
‘Vaccines are probably the most health-effective intervention you can give,’ says Powrie-Smith. ‘We spend trillions in building up the global economy and a virus like Covid-19 takes it down in the space of six weeks. Globally, governments have spent around US$96 trillion in response. For me, that focuses the mind on the absolute importance of biomedical research and expresses in an extreme way the links between health and the economy, and the value vaccine delivery has to health and society. This goes way beyond industry – it’s a societal issue.’
Yet vaccination isn’t the only way to benefit public health. A much wider question would consider why some vaccines are needed at all. A universal rule with diseases is that they disproportionately affect poorer communities; Covid-19 has shown that this applies in the high-income West as well as in developing nations. Populations living in poverty, without adequate sanitation and in close contact with infectious vectors and domestic animals and livestock are those worst affected by the cohort of neglected diseases. ‘The reality is that if people were less poor, then we wouldn’t have these [neglected] diseases,’ says Kieny, who points to the example of cholera. ‘Do you invest in a vaccine or in better public water supplies? Clearly, you need to do both. The question is whether you invest only in short-term fixes. For some diseases, it’s prudent to consider other interventions – develop treatments or invest in long-term measures to address poverty.’
This wider picture is recognised by MSF’s Martin. ‘Covid-19 is actually the latest in a long line of failures in public health. It seems that as a global community, we are not really invested in pandemic preparedness. Much of the Covid effort and R&D has been really good and it’s incredible to develop an efficacious vaccine basically within a year. But we could do with it in other areas. It would make a huge difference to so much public health in low-income countries.’
Others recognise a natural human trait of relaxing as immediate danger passes, but suggest the extremes of Covid may have a different legacy. ‘The first thing people want to do once a crisis is over is just forget about it,’ says Kieny, ‘but there’s a chance that things can change.’
On this at least, the pharma industry and NGOs are in agreement. ‘At some point, we need to take a break and analyse how these new positive ways of working can be incorporated into what we do in the future,’ says Powrie-Smith. ‘There is a collective responsibility to learn from this. Inevitably, some of these things will be forgotten, but there’s a real willingness to learn how we can do things better.'
MacGregor is optimistic that the impact of Covid-19 will prove visceral enough to change attitudes to public health in the longer term. ‘I would hope the lessons we learn involve some re-thinking about preparedness and about rebalancing the system so that it can prepare for future epidemics as well as wider health-system problems,’ she says. ‘We need ways to incentivise R&D that do not necessarily rely on making a profit. That sounds horribly idealistic, but Covid has given high-income countries rather a jolt at how these things can happen. In Africa, I think the concept is still strong that sudden death from an infectious disease can happen.’
Dengue affects 60 million people every year, but there is no prospect of a treatment, Kamal-Yanni points out. ‘It’s unlikely there’ll be the financial incentive to produce a treatment. Attitudes towards malaria might just change if it takes hold in southern Spain and elsewhere with climate change.’
Martin has similar concerns but tries to be upbeat. ‘We can’t keep going with the duct-tape approach to address market failures,’ he says. ‘My fear is that we will not learn from this pandemic and re-evaluate. But if I wasn’t optimistic, I wouldn’t do this job. There are some silver linings in all of this.’