Thanks to PATH, Serum Institute of India, research partners in Africa and India, a longtime funder, and others, a more affordable pneumococcal conjugate vaccine (PCV) is now part of the toolkit for fighting pneumonia—the world’s #1 infectious child killer—and other pneumococcal diseases.
Preclinical vaccine development
Clinical studies in low-resource settings
Regulatory strategy and WHO pre-qualification
Staff at work at Serum Institute of India’s PCV facility. Photo courtesy of Serum Institute of India, Pvt. Ltd.
Pneumonia remains the single biggest infectious killer of adults and children worldwide. Roughly 740,000 children die from it before their fifth birthdays each year, mostly in low- and middle-income parts of the world. That’s a young life lost every 39 seconds.
A complex foe
The most common cause of deadly childhood pneumonia is the pneumococcus. This bacterium is complex with at least 100 varieties (serotypes) and also causes meningitis, sepsis, and debilitating middle ear infections.
PCVs protect against some key serotypes and have helped reduce childhood deaths and illness where used. They are, however, among the most complicated and expensive vaccines to manufacture, so much so that only one other vaccine manufacturer managed to enter the market in the initial 20 years after the first PCV was licensed in 2000.
Barriers to PCV access
When left to natural market forces, few competitors and high production costs are a recipe for high prices. In the early years of PCVs, this was the case and only the richest countries could afford them.
Only with substantial financial support from donors like Gavi, the Vaccine Alliance and its pneumococcal Advance Market Commitment (AMC) financing mechanism did low-income countries begin rolling out PCVs in 2009. The AMC incentivized PCV producers to dedicate supply at discounted prices (no more than $3.50 per dose) for low-income markets. Though the AMC sunset in late 2020, its supply contracts are active until 2029.
Today, most Gavi-supported countries have introduced PCVs, but it took a global effort and the job is not complete. Millions of children still either don’t have or are at risk of losing access to PCVs—with vaccine price at the heart of the problem.
Many self-financing middle-income nations haven’t yet introduced PCVs because they remain cost prohibitive. Existing PCV programs are also at risk due to budgetary strain, especially for countries facing paying their own way after graduating from Gavi support (once national income exceeds Gavi’s eligibility threshold) or when Gavi support phases out. Additionally, PCV financing occupies disproportionate donor funds compared to other vaccines, limiting the ability to address other public health priorities.
These realities have long underscored the need for improving the inherent affordability of PCVs to reduce the burden on public health and donor budgets and ensure equitable and sustainable access.
In 2008, PATH and Serum Institute saw the needs and launched a vaccine development collaboration, funded in part by the Bill & Melinda Gates Foundation, to address them. MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine (LSHTM), and multiple study sites in India (see full list) bolstered the effort as central clinical research partners. Other pivotal contributions came from colleagues at UCL and other partners/consultants.
The shared vision was ambitious. We set out to develop a PCV that would be sustainably affordable for all low- and middle-income economies and protective against the pneumococcal serotypes causing the most disease and death in Africa, Asia, and Latin America—where pneumococcal disease claims the most lives.
And we succeeded.
After a decade of strong partnership, the resulting PCV, PNEUMOSIL®, focuses on serotypes threatening children in underserved countries, meets the high standard of performance expected of PCVs, is licensed and WHO prequalified, and is poised to reach more children by breaking down inherent price barriers to access.
Why was PATH chosen to do this work?
PATH is no stranger to developing successful and affordable vaccines. In fact, we had already partnered with Serum Institute (and WHO) on another low-cost conjugate vaccine that you may have heard of, MenAfriVac®, which has eliminated meningitis A epidemics in Africa's meningitis belt countries where it has been introduced.
This is just one of a variety of reasons why our funder has been supporting us since 2006 to advance the development of pneumococcal vaccines, including PNEUMOSIL. Here are a few more:
- Healthy partnering. We build long-lasting relationships and bring partners together across sectors and geographies to foster vaccine innovation and sustainable solutions that wouldn't otherwise occur.
- Dedication to advancing immunization equity. We have a long history of ensuring that the vaccines we work on are globally accessible and within reach of the people that need them, regardless of where they live or ability to pay.
- End-to-end vaccine expertise. PATH is one of very few organizations with the capacity to bring vaccines from discovery and development through delivery to the very last mile, with subject matter expertise every step of the way.
PNEUMOSIL provides hope that PCV protection will be able to reach more of the world’s underserved communities, sustain ongoing PCV programs, and help save more lives.
The task wasn’t easy. We had to improve the inherent affordability of a PCV while preserving performance, quality, and serotype coverage optimal for countries with high disease burdens in Africa, Asia, and Latin America. This was uncharted territory, so we started at the beginning.
Optimizing design and manufacturing
Predecessor PCVs have covered either 7 (first generation) or 10 to 13 serotypes (second generation), some relevant to Africa, Asia, and Latin America and some less so. For PNEUMOSIL, we included the 10 serotypes most likely to cause severe disease in these regions, including some that were emerging as urgent threats (serotypes 6A and 19A). This decision ended up being key for achieving a balance of serotypes that matched or exceeded other PCVs in terms of disease coverage and helped keep manufacturing costs as low as possible.
Serum Institute achieved further affordability by optimizing several processes for large-scale manufacturing that lowered costs while maintaining high vaccine quality. These breakthroughs included improving conjugation efficiency and carrier protein and polysaccharide production as well as developing an efficient formulation process at large scale.
With our newly designed product, it was time to test it in the lab. Serum Institute led preclinical studies with support from PATH to assess initial safety and immune responses, with promising results.
Parallel clinical study pathways in Africa and India
With positive preclinical results in hand, the next step was to see how the vaccine performed in people. As we crafted the strategy, we realized that the best way to generate data from different representative geographies and to accelerate the pathway to the dual project objectives of Indian marketing authorization and WHO prequalification would be via two parallel clinical development programs—one in Africa and one in India.
So, PATH partnered with longtime pneumococcal vaccine research stalwart MRC Unit The Gambia at LSHTM to deliver high quality Phase 1/2 and Phase 3 clinical trials in The Gambia to generate the key safety and immunogenicity data needed for WHO prequalification; while Serum Institute sponsored Phase 1, 2, and 3 clinical trials in India in collaboration with various trial sites to support Indian marketing authorization.
This creative dual-pathway approach was highly successful and collectively provided the data package needed to meet both objectives. Not only did the vaccine have a good safety record, but it was shown to perform on par (or better in some regards) with the other WHO-prequalified PCVs.
We couldn’t have gotten far without a diversity of other collaborators across continents that shared the vision for a high-quality, low-cost PCV. For instance, all serology testing for both African and Indian clinical trials took place in Dr. David Goldblatt’s WHO Reference Laboratory for Pneumococcal Serology at the Great Ormond Street Institute of Child Health, University College London. Other contributions came from clinical research organizations, regulators, governments, consultants, and our funder.
More information on the approach to developing PNEUMOSIL and collaborators can be found in Human Vaccines and Immunotherapeutics.
PNEUMOSIL received WHO prequalification in December 2019 and Indian marketing authorization in July 2020. With these achievements, the vaccine is now being used in India’s Universal Immunization Programme and introductions or switches have been rolling out in other countries since 2020.
Incredibly, Serum Institute is making PNEUMOSIL available to Gavi and other low- and middle-income economies for just $2 per dose—roughly 30% less than Gavi prices for other PCVs and dramatically less than PCV prices typically available to non-Gavi countries.
What's more, Serum Institute entered into an agreement in June 2020 to supply 100 million doses of PNEUMOSIL over 10 years via the pneumococcal AMC.
The vaccine is indicated for both WHO-approved dosing schedules—two primary doses and a booster dose (2+1) and three primary doses (3+0)—as well as a 3+1 schedule. Pneumosil's authorization for use in both WHO-approved schedules gives countries more options when considering PCV use and scheduling within their specific routine immunization contexts. Clinical studies in India and The Gambia informed the dosing schedule approvals.
Generating additional information on PNEUMOSIL
Now that we have a more affordable PCV with the potential to do immense good, countries need further information for PCV program decision-making, including for PNEUMOSIL. So, we're continuing to study PNEUMOSIL.
With support from PATH, Serum Institute will be looking at the degree to which PNEUMOSIL affects the pneumococcal bacteria carried in a vaccinated person's nose, a measure of disease transmission and herd immunity potential.
What it all means
PNEUMOSIL’s market entry is an important milestone toward enhancing the world’s arsenal of state-of-the-art PCVs and alleviating the price and supply barriers that have historically hindered or precluded sustainable access for many low- and middle-income countries.
For Gavi and the countries it supports, the savings that PNEUMOSIL provides means public health funds can go farther against pneumococcal disease and other health priorities. Most of all, PNEUMOSIL will help save more lives by enhancing global protection against pneumococcal disease, including pneumonia—the #1 infectious killer of children worldwide.
PATH’s role supporting PNEUMOSIL's early development and clinical trials in The Gambia was funded by the Bill & Melinda Gates Foundation. The Indian clinical development program was funded and conducted by Serum Institute.
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