Time well spent: The complex journey of a life-saving vaccine

First, some background: Streptococcus pneumoniae, also known as pneumococcus, is a bacterium that can cause pneumonia, meningitis, and sepsis, as well as the common ear infection. It hits young children particularly hard. An estimated 400,000 children under age 5 die each year from pneumococcal disease, mostly due to pneumonia.

Health experts had long believed that a vaccine targeting this bacterium could save millions of children’s lives. But making the first safe and effective pneumococcal vaccine for young children would prove challenging.

First, the pneumococcus has nearly 100 serotypes, or strains, and different serotypes are prevalent in different regions of the world. While the first PCV was available in 2000, it would take another nine years for a vaccine targeted at strains prevalent in low- and middle-income countries to become available.

And there was another catch: Conjugated vaccines—that’s what the C in PCV stands for—are expensive to make because conjugation, which involves coupling a protein and a polysaccharide, is a complex, multi-step process. While some childhood vaccines cost just pennies to produce, a course of the 2009 PCV vaccine could cost well over US$40 per child, putting it out of reach in many places. That left millions of children without a viable way to get this protection.

In anticipation of a PCV vaccine suitable for low- and middle-income countries, in 2008 an expert committee of the Indian government, called the National Technical Advisory Group on Immunization (NTAGI), began evaluating the potential introduction of a new PCV. Such a decision is not simple for any country. First, it involves determining whether the vaccine addresses an actual problem: How many children are sickened by pneumococcus? How does that compare with other causes of childhood death or illness? Also, what are the costs? What won’t get funded if we add this vaccine? For India, gathering this information would take time.

The issue wasn’t whether pneumonia was a significant problem among Indian children; that was already clear from local disease burden estimates. But of the several types of pneumonia, PCVs addressed only one, pneumococcal pneumonia. So the real question was, were large numbers of Indian children dying from pneumococcal pneumonia? Also, which serotypes were causing disease in India—and were they the same serotypes targeted by PCVs? Indian researchers set out to tackle the questions from different angles.

Detecting pneumococcus is challenging. Pneumonia affects the lungs, but the lung isn’t easily accessible for tests. Pneumococcus often doesn’t show up in blood tests, either. That leads many health care providers to logically conclude that their patients don’t have pneumococcal pneumonia.

But some researchers suspected that blood tests weren’t providing a true picture, so in addition to looking at blood specimens from pneumonia patients, they evaluated blood and cerebrospinal fluid from meningitis patients, where pneumococcus may be found more frequently. Knowing that pneumococcus can lurk far back in the nasal cavities of both healthy and sick children (and is a precursor of disease), they looked for it in children’s noses. Sure enough, they found pneumococcus.

This multipronged effort paid off, clearly demonstrating that the bacterium was circulating in the community and had the potential to cause serious illness. Not only that, but the samples revealed that the serotypes present in India could be targeted with a vaccine.

Shally Awasthi, a doctor and professor at King George’s Medical University (KGMU) in Lucknow, India, took another approach to the problem. As a researcher who had studied pneumonia for decades, she knew that studies done globally had identified X-ray features that were characteristic of pneumococcal pneumonia. So her team at KGMU designed a study looking for these indicators. They would eventually scrutinize X-rays of thousands of children.

“Early on, we knew pneumonia was a problem, but we didn’t know if it was pneumococcal pneumonia,” Dr. Awasthi said. But when they looked at the data, they saw the truth. “We had findings in about 30% of the X-rays, meaning pneumococcus was the likely cause of the child’s illness,” she said. “This was amazing to me.”

Amazing because it meant that pneumococcus was responsible for many more pneumonia cases than doctors had realized, and many of these cases could be prevented.

While researchers were learning more about the significance of pneumococcal disease in India, the broader public didn’t yet understand the seriousness of the problem.

Mathu Santosham, a doctor and Johns Hopkins University medical researcher, was among those who helped gather the evidence and raise awareness. For decades, Dr. Santosham had devoted his career, working in both the U.S. and India, to reducing childhood mortality through vaccines, so he knew that many segments of the Indian population had historically been hesitant about vaccines. He also knew that even some health care providers didn’t know that the pneumococcal bacterium played a big role in pneumonia deaths, because they’d so rarely seen a positive blood test. Starting around 2008, he joined others interested in PCV. At that point, some portions of the community still weren’t certain that injecting children with yet another vaccine was necessary or safe.

“But I knew that all of us agreed we wanted to reduce childhood mortality,” Dr. Santosham said. “We just needed to talk about the things we could do to achieve that.”

The Indian government had been doing significant work to raise awareness of childhood diseases and raise public trust in vaccines. Even Indian celebrities got involved, some writing opinion pieces highlighting the benefits of childhood immunization. Cricket matches were organized featuring celebrities, public representatives, journalists, and researchers, to generate awareness of the impacts of infectious diseases, including pneumonia and diarrhea, that took so many young children’s lives. Organizers highlighted the great strides the Indian government had made in reducing childhood mortality through a variety of measures, while urging parents to vaccinate their children.

In 2014, the government introduced five new lifesaving vaccines into its universal immunization program. By that point, it had already successfully eliminated wild polio. Under its flagship program, Mission Indradhanush, it had also committed to intensifying its immunization program to ensure equitable vaccine access to all Indians, whether they lived in urban centers or rural regions.

At the same time, additional evidence about pneumococcal disease had been building. In 2014, Dr. Santosham co-chaired an international symposium in India during which researchers, doctors, and officials reviewed some of this evidence. Other countries at all income levels had begun introducing PCVs and were seeing significant drops in pneumonia deaths. It was becoming clear that pneumococcus was responsible for at least 30% to 60% of serious pneumonia cases.

In 2015, NTAGI recommended that a PCV be introduced in India. Within seven months, the Indian government approved the recommendation, making it one of the fastest vaccines from evidence presentation to policy decision. Jayaprakash Muliyil, an NTAGI member, characterized it this way: “India’s approach was science based, so that public health initiatives were based on proper prioritization and principles of social justice.”

Still, the affordability issue lingered. With 27 million babies born every year in India and the high price tag for available PCVs, nationwide scale-up was still too expensive. This wasn’t just an issue for India; other countries around the world also faced an affordability challenge.

“The introduction of PCV into the public health systems of low- and middle-income countries was rather slow,” Dr. Muliyil said. “The process involved high degrees of cooperation with higher-income countries and generous support from various funding agencies.”

One of the supporters was Gavi, the Vaccine Alliance, which had joined with the World Bank and other donors to devote significant resources to pneumococcal disease. In 2009, Gavi launched the Pneumococcal Advance Market Commitment, an innovative financing mechanism that, among other things, reduced the risk for vaccine manufacturers and incentivized the creation of new, less expensive PCVs. As India laid the groundwork for PCV introduction, those efforts were in progress. Gavi also helped low- and middle-income countries access PCVs to vaccinate their children. Over time, more and more countries began adding PCVs to their routine immunization schedule.

In India, after the government concluded that a PCV would significantly curtail child mortality, it secured partial assistance from Gavi for its initial introduction. In 2017, India began introducing a PCV in the states where the most children were stricken with serious pneumonia. By focusing on the highest-burden states first, India would be able to reduce childhood mortality significantly as it geared up to reach the entire population.

“It was indeed a very proud moment,” said Mangla Sood, an immunization officer in the health department of Himachal Pradesh state when the vaccine was introduced there. “With the PCV vaccine as part of immunization program, the number of children being hospitalized for pneumonia has been reduced. That also reduced the economic burden on families and the health cost burden on the country.”

Meanwhile, another effort was coming to fruition.

In 2008, the Serum Institute of India, Pvt. Ltd. (SIIPL), along with PATH, a Seattle-based nonprofit, had come together with a grant from the Gates Foundation to begin creating an entirely new PCV targeting the serotypes causing the most invasive pneumococcal disease deaths and illness in Africa, Asia, and Latin America. It was an ambitious plan. Over the years, several pharmaceutical companies had tried, unsuccessfully, to develop new pneumococcal vaccines for children. On top of the scientific challenges, the two organizations also aimed to make this highly complex vaccine at a much lower price.

PATH and Serum Institute were uniquely suited to the task. PATH had experience in vaccine development. Serum Institute is the world’s largest vaccine manufacturer by number of doses produced, and it specializes in creating extremely cost-effective vaccines.

Based on studies done in India and in other low- and middle-income countries, PATH and Serum Institute decided to make a vaccine addressing 10 pneumococcal serotypes found in these regions. “It's basically 10 different vaccines that have to be made and then put together,” said Mark Alderson, director of PATH’s pneumococcal project. Of course, the conjugation process added to the complexity. “There are literally hundreds of quality control tests that have to be conducted,” Alderson said. “So, this is very, very technically challenging to do.”

By 2015, the partners were ready to begin clinical trials, choosing locations in the areas of greatest need: Africa and Southeast Asia. Serum Institute led the work in India, and PATH sponsored the trials in West Africa, which were conducted by a health research organization called the MRC Unit The Gambia at the London School of Hygiene & Tropical Medicine.

When the results of the pivotal Phase III clinical trial in Gambia were unveiled, the vaccine met or exceeded the licensing requirements on every measure.

Based on all the data, the new vaccine received Word Health Organization (WHO) prequalification status in 2019, meaning it was deemed safe and effective and could be used in international programs such as those run by UNICEF and Gavi. In 2020, the Indian government approved the vaccine for use nationwide.

Pneumosil, as the vaccine is called, is an Indian success story. It is produced in India, by an Indian company, and is being made available globally to low- and middle-income countries for US$2 per dose. At US$6 per child for the three-dose course, it costs about 30% less than the other PCVs available through Gavi. “It’s quite a tour-de-force from the manufacturing standpoint,” Alderson said, “and a lot of credit goes to Serum Institute for it.”

This affordability would allow India to accelerate its plan for PCV expansion to all of its states, so all of its newborns could be protected from pneumococcus. But first it would have to confront a new challenge.

Although the decision to roll out a PCV in India was the culmination of years of work, some would argue that the work was just beginning. Successful implementation of any new vaccine introduction entails an enormous, but often unrecognized, effort. In this case, it required scaling up a digital platform nationwide to monitor the vaccine supply chain, strengthening surveillance systems to monitor adverse immunization events, and enhancing the network of cold-chain equipment. All this work was led by the Indian government, with the involvement of WHO, UNICEF, JSI, and other partners.

In addition, those who would be more directly involved in administering Pneumosil would have to be trained, including some 32,000 medical officers, 20,000 cold-chain handlers, and more than 150,000 vaccinators.

While Indian public health workers are experienced in large-scale vaccine introduction, the COVID-19 pandemic would pose new, unprecedented challenges. Like many countries, the COVID-19 vaccination campaign was important in India, a country particularly hard hit by the pandemic. Initially, some officials feared that the PCV rollout would interfere with the country’s COVID-19 vaccine campaign. But the teams were committed, managing COVID-19 vaccinations during the day and working virtually, late into the evenings, to prepare for the PCV program expansion.

Deployment happened with remarkable speed. By October 2021, PCVs were being administered to infants in all Indian states, free of charge, as part of the national immunization program. Gavi estimates that the vaccine will prevent the deaths of around 50,000 Indian children under age 5 each year.

The new vaccine will help in other ways, too. Before, about half of Gavi’s vaccine budget had been consumed by its PCV programs globally. With a lower-priced PCV available from India, more room in the budget has become available for other vaccines. That means more children in low-income countries can be protected from other devastating illnesses, too.

It’s an achievement not only for India, but for the world.