17 Mar The promise of reduced dose pneumococcal vaccination for children
Pneumonia is the leading infectious cause of death in children under five and, as a result, the pneumococcal conjugate vaccine, or PCV, is one of the most lifesaving vaccines. However, just six in every ten children are protected with PCV well below the global target of 90%, according to official UN estimates. Further, many of countries with the largest numbers of childhood pneumonia deaths have the lowest PCV coverage rates (e.g., India, Nigeria, Indonesia). Of great concern, the PCV has not even been introduced in countries like Chad, Guinea, Somalia, South Sudan, Egypt, China, and Viet Nam where collectively, 64,000 children die each year from pneumonia, according to the Global Burden of Disease.
One of the reasons for such low coverage of a lifesaving vaccine is its high cost. The PCV is the most expensive childhood vaccine and helping low-income countries afford it cost Gavi, the Vaccine Alliance $US4 billion between 2009 to 2020, more than any other vaccine. As countries grow and graduate from Gavi support, there are concerns about their ability to sustain the high costs of their PCV programs, while countries who are ineligible for Gavi support continue to cite high cost as a barrier to PCV introduction. The latest World Health Organization (WHO) Global Vaccine Market Report highlighted the PCV as an example of a vaccine with “poor market health,” citing as evidence the market dominance (80%) of just two vaccines (Pfizer and GSK), the wide variation (18-fold) in PCV prices, and the sharp increase (%) in price in recent years. Concerns about high PCV prices have even motivated the World Society for Pediatric Infectious Diseases (WSPID) to launch a Call to Action for Fair Vaccine Prices, with more than 500 organizations signing on.
In the context of high and rising PCV prices, new evidence on the effectiveness of reducing the dosing schedule from three or four doses to two holds much promise. A new group of studies are measuring what happens to two different groups of children vaccinated with the same PCVs at different times. The first group of children typically receive a PCV three times a year (at 2, 4 and 6 months, or 2, 4, and 12 months) in what is called a 3+0 or 2+1 dosing schedule. The other group of children get a PCV just twice (at 2 and 12 months, or 6 weeks and 9 months) in what is called a 1+1 schedule. The first dose/s are called “primary” doses, while the final dose is called the “booster” dose.
After vaccination, both groups of children are tested to see if there are differences in “immunogenicity” and “nasopharyngeal carriage.” Did two PCV doses provoke a weaker immune response in the children with less impact on pneumococcal bacteria in the nasopharynx, the upper part of the throat behind the nose? If two PCV doses are not as effective as three at stimulating the immune system to produce antibodies and at reducing the presence of pneumococcal types in the children’s throats, three doses are clearly needed. The vaccines used in these studies typically include GSK’s PCV10 (Synflorix) and Pfizer’s PCV13 (Prevenar).
What are the two-dose PCV dosing studies saying?
The studies that have either already reported or are underway include three in high-income countries (UK and Canada), four in middle-income countries (South Africa, India, Vietnam), and one in a low-income country (The Gambia). In 2018, the UK study found that the 1+1 schedule was equivalent or superior to the 2 + 1 schedule and concluded that, “introducing a 1 + 1 schedule in countries with a mature PCV programme and established herd immunity is likely to maintain population control of vaccine-type pneumococcal disease.” As a result, the UK introduced a 1+1 schedule in 2020 and a recent assessment found that pneumococcal disease incidence was lower in 2022 than in 2019. The Canadian study is comparing 2+1 and 1+1 and has not yet reported results.
The studies in South Africa, India, and Viet Nam have all reported comparable immunogenicity in both the 2+1 and 1+1 groups. The South African study concluded, “the non-inferiority in post-booster immune responses following a single-dose compared with a two-doses of PCV13 or PCV10 indicates the potential for reducing PCV dosing schedules from a 2 + 1 to 1 + 1 series in low-income and middle-income settings with well established PCV immunisation programmes.” A subsequent analysis found that the serotype-specific colonization data also support transitioning to a 1 + 1 schedule in South Africa and recommended ongoing monitoring of colonization immediately before and after transitioning.
The India study concluded that immune protection from 1 + 1 schedules is comparable to WHO-recommended 3-dose schedules, and the first Viet Nam study in Ho Chi Minh City found that a 1 + 1 PCV schedule, “greatly reduces vaccine-type carriage and is likely to generate substantial herd protection and provide some degree of individual protection during the first year of life.” The second Nha Trang study is currently testing the 1+1 schedule compared to the WHO standard 2+1 and 3+0 schedules, and exploring the impact of a single dose schedule. The Gambia trial is expected to report this year.
What about one-dose PCV in humanitarian settings?
In addition to these routine vaccination studies, there are others looking at the impact of just one dose of PCV for children living in fragile settings in Niger, Kenya, Burkina Faso, and Somaliland. In the Epicentre/MSF study in Niger and Kenya, children aged one to nine years will be divided into groups with some getting one full PCV dose and others a fractional dose (20% of a single dose). In the Burkina Faso study, children under five will receive one dose, and in the Somaliland study, children under five living in the Digaale camp for Internally Displaced Persons (IDP) will get one dose. There is also a fractional dose trial underway in Kenya where some children will receive a full PCV dose, while others get 2/5 or 1/5 the dose. Unlike the routine vaccination studies, two of the humanitarian studies will use the Serum Institute of India’s PCV 10 (PNEUMOSIL). The results of these studies will be extremely important to Gavi as it develops its 6.0 Strategy and grapples with how to deliver vaccines when government service provision is compromised or non-existent.
What else can be done to reduce the costs of PCV programs?
Reducing PCV dosing schedules is not the only way to improve the financial sustainability of PCV programs. Countries can elect to switch to the Serum Institute of India’s PCV10; with a Gavi price of $US2.00 per dose it can cut costs by one third, but so far few have. The Serum Institute has recently offered Latin American countries who are members of the Pan-American Health Organization (PAHO) the Gavi price. Gavi could go further and extend its PCV price to currently ineligible low- and middle-income countries with large numbers of childhood pneumonia deaths. Increased efforts to improve market competition by supporting companies to develop more cost-effective PCVs is also needed. The Bill & Melinda Gates Foundation is currently supporting a new low-cost 25-valent PCV (IVT PCV-25) from US company Inventprise is currently in clinical trials, and Australian company GPN Vaccines is also working on a new pneumococcal vaccine.
Is it too early to call for more countries to switch to two PCV doses?
So far, the UK is the only country to switch to two PCV doses. While an academic consensus seems to be emerging that the majority of the infant population will have good protection from a two-dose PCV schedule, concerns remain that immuno-compromised children (e.g., malnourished, HIV positive, etc.) could still benefit from additional PCV doses. Experts also caution that low compliance with the booster dose could undermine impact, and that governments will need robust disease surveillance to monitor cases of serious disease between primary and booster doses. In the coming year, as more and more evidence arrives from African and Asian settings, governments need to pay attention. With new vaccines for malaria, HPV, and RSV on their doorsteps, and the vaccine pipeline growing every year, the fiscal space for new vaccines is shrinking. And with the 2030 Sustainable Development Goal deadline fast approaching, governments need to find ways to simultaneously reduce the cost of their childhood vaccine programs and accelerate child mortality reductions. Reducing the PCV schedule could be one of them, especially if the cost savings from a 1+1 schedule were used to increase vaccine coverage of PCV or other vaccines. Of all countries, South Africa may be well placed to move first, for the second time. It was the first African country to introduce PCV back in 2007 and the first African country to achieve a 90% reduction in pneumococcal disease a decade later. Could it be the first to switch to a 1+1 PCV schedule, with other nations to follow?
View summaries of all of the current studies on one simple table here.
Published for the 13th Meeting of the International Society of Pneumonia and Pneumococcal Diseases (ISPPD), 17-20 March 2024
Updated July 2024