Noida: In less than two years from the start of the Covid-19 pandemic, the world had seven vaccines. In contrast, there has been only one tuberculosis (TB) vaccine in the last 100 years, and one malaria vaccine in 130 years since the malaria parasite was named. Why have vaccines for some diseases taken so long?
Experts point to scientific challenges in vaccine development, because of the germ that causes these diseases, and relatively lower research funding for TB and malaria as compared to Covid-19--in 2020, just the US funded Covid-19 research was 1.7 times India's health budget while TB received less than a tenth of that amount globally.
Some diseases get preference over others for vaccine development, as do countries in access to vaccines, exacerbating health inequalities, experts said.
Covid-19 killed 1.9 million in 2020 and the World Health Organization (WHO) approved its Covid-19 vaccine a year after China alerted it about an outbreak of the virus. Tuberculosis (TB) killed 1.2 million globally in 2020, but its vaccine is 100 years old and has low efficacy. A vaccine for malaria--which killed 409,000 in 2019--came 130 years after the malaria parasite was named. HIV-AIDS, which killed 680,000 cases in 2020, has no vaccine, even 40 years after it was discovered.
"TB is a disease of the poor, and malaria is a disease that affects the poor parts of the world. Investing in a vaccine for the poor makes no sense for companies if they intend to make obscene profits," said Gagandeep Kang, a virologist and professor at the department of gastrointestinal sciences at the Christian Medical College in Vellore.
Our explainer examines why it was easier to develop a Covid-19 vaccine as compared to the ones for malaria and TB.
Current TB and malaria vaccines have low efficacy
The current vaccine for TB, the bacille Calmette-Guérin (BCG), uses a weakened form of the live TB bacteria, and was created almost 100 years ago. It prevents severe forms of TB in children, but can only prevent half of all infections, and is not very effective in adults.
The new malaria vaccine that the WHO approved took 30 years to develop. Though it is a breakthrough, it does not meet the WHO's goal for a malaria vaccine efficacy of 75%. In three countries--Malawi, Kenya and Ghana--where 2.3 million doses of the vaccine have been given to 800,000 children in two years from 2019, the vaccine reduced malaria cases by 40% and prevented one in 200 deaths, according to a WHO fact sheet for the vaccine. The WHO recommends a minimum of four doses of the vaccine to be given to children from five months of age in places with high incidence of malaria.
In contrast, the minimum efficacy threshold for the WHO to approve Covid-19 vaccines is 50%. The vaccines in use in India, Covishield and Covaxin, have an efficacy of 76% and 78% against symptomatic disease, respectively. Pfizer's Covid-19 vaccine and Moderna's vaccine have an efficacy of 95% and 94%, respectively.
Further, the new malaria vaccine targets only one strain of the malaria parasite, plasmodium falciparum. It does not offer protection against the other strain of the malaria parasite found in India, plasmodium vivax. Another malaria vaccine in advanced stages of development, the R21/MM, also targets the plasmodium falciparum.
Unequal funding for research on different diseases
Not all countries bear an equal burden of all diseases. Developing countries, such as those in Africa and South Asia, have more cases of TB and malaria, as compared to richer countries. For instance, the only available TB vaccine is not recommended for everyone in the US--like it is for India--because of the low risk of getting infected with the TB-causing bacteria in the US. Covid-19, on the other hand, impacted the entire world, with some rich countries impacted more than developing ones.
Global funding for Covid-19 research was multiple times the funding for malaria and TB. The US Congressional Budget Office alone allocated $19 billion for vaccines for Covid-19 in 2020, including advance payments for vaccine doses.
In contrast, the whole world collectively spent less than a billion dollars on all TB research in 2019, of which $117 million was for vaccines. Malaria research got $603 million in 2019, of which $135 million was for vaccines.
The Indian government also supported Bharat Biotech's Covaxin, which was developed in collaboration with the Indian Council of Medical Research, the government's apex scientific research body, and the Oxford/AstraZeneca vaccine, sold in India as Covishield.
We reached out to the Indian government for information on expenditure on research on vaccines for TB, malaria and HIV/AIDS. The story will be updated when they respond.
"Covid was a great example of a mobilisation of efforts and resources for developing a vaccine against a disease," said Bhavana Lall, who works in public health, and is a clinical assistant professor at the Department of Clinical Sciences at the University of Houston in the US. "Everyone from the scientific community, to donors and healthcare workers, came together with an urgency that was of course required during the pandemic but is also required against other diseases."
"We don't need to wait for over 100 years to access new TB vaccines, but like with Covid-19, increased investments can be a game-changer and alleviate the suffering and deaths caused to millions due to TB--that remains one of the world's top infectious killers," said Tereza Kasaeva, director of WHO's Global TB programme, at an event marking 100 years of the TB vaccine.
The new malaria vaccine, the RTS,S, approved by the WHO in October 2021, was developed through a partnership between the pharmaceutical company GlaxoSmithKline (GSK) and the health non-profit PATH Malaria Vaccine Initiative (MVI), with support from the Bill & Melinda Gates Foundation and a network of African research centres. The pilot programmes of the vaccine in Kenya, Malawi and Ghana were funded with $15 million given by The Global Fund to Fight AIDS, Tuberculosis and Malaria. Aid organisations including GAVI, a global vaccine alliance, and UNITAID, a global health organisation, have committed up to $27.5 million and $9.6 million, respectively, for the first four years of the implementation of the vaccine programme.
But overall, malaria prevention through vaccines received lower funding than the Covid-19 vaccine effort, with $742 million invested between 2007 and 2011. Drugs for malaria received $1 billion over the same period.
New vaccines are required for TB and malaria, which need both funding and favourable market forces, said Prashant Yadav, affiliate professor of technology and operations management at the Institut Européen d'Administration des Affaires (INSEAD) in France. "When vaccine and therapeutic developers know there is a large guaranteed market, they make large investments in those therapeutic development programmes," he explained.
For instance, for Covid-19, governments had signed advance purchase agreements with pharmaceutical companies, even before the vaccines had been approved by regulatory bodies. This enables pharmaceutical companies to take the risk associated with new vaccine development.
The Indian government paid an advance of Rs 4,600 crore to the manufacturer of Covishield, the Serum Institute of India, and Bharat Biotech, to help them ramp up capacity. The US paid an advance to Pfizer/BioNtech of $5.9 billion.
Scientific challenges in vaccine development
It is not just the decisions countries make but the difference in the organism that causes these diseases that also makes it more challenging to make vaccines, such as that for HIV-AIDs.
For a vaccine to be effective, it must spur the body to produce antibodies which fight against the disease or, it must make the body produce cells and specific proteins that help the body identify and kill infected cells, or both, said Kang, the virologist.
To do so, vaccines either contain inactivated pathogens (like the injectable polio vaccine that contains weakened poliovirus not capable of causing disease), or spike proteins (a protein molecule on the surface of the virus that helps it to bind to the cells it intends to infect), like the Moderna and Pfizer-BioNTech vaccine for Covid-19).
The more complex the disease-causing germ, the harder it is to target them using vaccines, said Kang. This is the case with both TB and malaria.
The TB-causing Mycobacterium Tuberculosis evades and exploits different cell subsets, to persist and cause disease, according to a paper published in August 2016 by authors from the University of Oxford.
Nearly a hundred years later, results from a trial of a protein-based vaccine for TB, called the M72, were published by scientists from South Africa, Zambia, the UK, Switzerland and the USA in December 2019. In 2020, the Bill and Melinda Gates Foundation was licensed to continue the trials for the vaccine.
There are also 13 other new TB vaccines in clinical trials: In all, there are three vaccine candidates in Phase I, which test for safety in small groups of people, eight in Phase II and three in Phase III, where the vaccine is given to a larger group and its safety and immune response is evaluated, according to the WHO's 2019 TB report.
What makes it hard to make malaria vaccines is that malaria parasites have a "complex life cycle, and there is poor understanding of the complex immune response to malaria infection," according to the US Centers for Disease Control and Prevention. Further, unlike the diseases for which we currently have effective vaccines, exposure to malaria parasites does not confer lifelong protection, the CDC said.
"Viral vaccines are the simplest, conceptually. We just have to stop the virus from entering the cells, which can be done by targeting a few proteins on the surface of the cell," said Kang.
But in the case of HIV-AIDS, "within three months of being infected, the virus in their body is different from the virus they were exposed to", said Kang. This rapid evolution within a host creates new species called "quasi" species and makes it difficult to create a vaccine against the virus, she explained.
Fifteen vaccines for AIDS are in various stages of trial at present, according to the advocacy group Global Advocacy for HIV prevention. Two other vaccines are in phase III trials, which means that they are now being given to large groups of people who are susceptible to the disease.
On the other hand, a combination of money, luck, technological advances and collaborations facilitated the formulation and trials of Covid-19 vaccines in less than a year, we had reported in December 2020. Covid-19 vaccines use a number of technologies; Bharat Biotech's Covaxin uses an inactivated virus, while Pfizer and BioNTech's vaccines use a small Ribonucleic Acid (RNA), which is injected into the cell with the blueprint of the protein.
There are 117 other Covid-19 vaccine candidates at different stages of trials and another 194 in early stages of development.
Unequal access to vaccines
After vaccine development, which countries get access to the manufactured vaccines also impacts global health inequality, experts said.
In Nigeria, the country with the lowest vaccination rate, 1.5% of its population is fully vaccinated against Covid-19 vaccine, whereas 67.5% of the population of the UK is fully vaccinated, according to Our World in Data, a compilation of global data by researchers from the University of Oxford.
"Low income countries still haven't vaccinated their healthcare workers [with the Covid-19 vaccine] and they have to deal with TB, malaria and AIDS as well," said Lall of the University of Houston. "There should be a clearly agreed upon global access plan which all funders of vaccines or therapeutics, both public and private, should agree to with the vaccine developer," said Yadav of INSEAD.
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