Duration of protection and density of colonisation following pneumococcal conjugate vaccination with a booster dose
Lead Research Organisation:
London Sch of Hygiene and Trop Medicine
Department Name: Unlisted
Abstract
In many countries, the use of pneumococcal conjugate vaccine (PCV) has effectively controlled pneumococcal disease caused by the pneumococcal serotypes included in the vaccines. PCV schedules generally use three or four doses. PCV given in early infancy provides protection from disease and priming of the immune system for response later in life. Later doses, between 9 and 18 months of age, result in a substantially greater immune response, termed a 'booster' response.
Despite the availability of PCV, global control of pneumococcal disease is hampered by cost. The GAVI Alliance provides subsidised vaccines for low-income countries. GAVI will spend 2.8 billion USD on PCV in the next 5 years and country co-payments to GAVI are substantial. As countries' Gross National Income increases so do their co-payments and at a threshold they become ineligible for subsidised vaccine. More than 20 countries are projected to 'transition' from GAVI support in the next 5 years. Continuation of PCV programmes will require countries to substantially increase their expenditure on PCV. Cost has also prevented most middle-income countries from introducing PCV. As a result, approximately half of children worldwide have no access to PCV. Reducing the doses and cost of PCV schedules will increase global PCV coverage and sustainability.
The Gambia introduced PCV in 2009 using a routine three-dose schedule without a booster dose (i.e., a '3+0' schedule), with resulting large reductions in invasive pneumococcal disease (IPD) due to vaccine-type (VT) pneumococci and severe pneumonia. Now that VT IPD is controlled, a large epidemiological study began in 2019 in rural Gambia to compare the ongoing use of the 3+0 schedule to a two-dose schedule that includes a booster dose at 9 months of age (i.e., a '1+1' schedule). Theoretically, the 1+1 schedule will stimulate greater herd protection in the community given its likely greater effect to prevent acquisition of pneumococcal bacteria in the nose. The UK Joint Global Health Trials scheme and the Gates Foundation are funding the study. This epidemiological study measures the effect of the two schedules on acquisition of pneumococcal carriage to 18 months of age as well as immunological measures.
The proposed study will determine key unknown factors regarding, a) the duration of the effect of the booster dose to reduce acquisition of pneumococcal carriage, b) the effect of the booster dose on the density of pneumococcal colonisation in the nose, and c) whether immunological measurements are associated with PCV protection against acquisition of pneumococcal colonisation. This knowledge will assist the interpretation of the results of the large epidemiological study, providing understanding of the reasons for its outcome.
The proposed study will extend follow-up of 784 children receiving the two schedules from 18 to 28 months of age. We will take nasopharyngeal specimens each month between 23 and 28 months of age and measure the difference in rate of pneumococcal acquistion between groups. One month after administration of the booster dose we will measure the difference in density of pneumococcal colonisation between groups, as density is likely related to transmission from person to person. Finally, we will perform additional functional tests of anti-pneumococcal immunoglobulin G at 10 and 18 months of age and determine whether immunoglobulin G concentration or function best correlate with later rates of pneumococcal acquisition. These data will be critical to international and national review of recommendations for PCV scheduling.
Despite the availability of PCV, global control of pneumococcal disease is hampered by cost. The GAVI Alliance provides subsidised vaccines for low-income countries. GAVI will spend 2.8 billion USD on PCV in the next 5 years and country co-payments to GAVI are substantial. As countries' Gross National Income increases so do their co-payments and at a threshold they become ineligible for subsidised vaccine. More than 20 countries are projected to 'transition' from GAVI support in the next 5 years. Continuation of PCV programmes will require countries to substantially increase their expenditure on PCV. Cost has also prevented most middle-income countries from introducing PCV. As a result, approximately half of children worldwide have no access to PCV. Reducing the doses and cost of PCV schedules will increase global PCV coverage and sustainability.
The Gambia introduced PCV in 2009 using a routine three-dose schedule without a booster dose (i.e., a '3+0' schedule), with resulting large reductions in invasive pneumococcal disease (IPD) due to vaccine-type (VT) pneumococci and severe pneumonia. Now that VT IPD is controlled, a large epidemiological study began in 2019 in rural Gambia to compare the ongoing use of the 3+0 schedule to a two-dose schedule that includes a booster dose at 9 months of age (i.e., a '1+1' schedule). Theoretically, the 1+1 schedule will stimulate greater herd protection in the community given its likely greater effect to prevent acquisition of pneumococcal bacteria in the nose. The UK Joint Global Health Trials scheme and the Gates Foundation are funding the study. This epidemiological study measures the effect of the two schedules on acquisition of pneumococcal carriage to 18 months of age as well as immunological measures.
The proposed study will determine key unknown factors regarding, a) the duration of the effect of the booster dose to reduce acquisition of pneumococcal carriage, b) the effect of the booster dose on the density of pneumococcal colonisation in the nose, and c) whether immunological measurements are associated with PCV protection against acquisition of pneumococcal colonisation. This knowledge will assist the interpretation of the results of the large epidemiological study, providing understanding of the reasons for its outcome.
The proposed study will extend follow-up of 784 children receiving the two schedules from 18 to 28 months of age. We will take nasopharyngeal specimens each month between 23 and 28 months of age and measure the difference in rate of pneumococcal acquistion between groups. One month after administration of the booster dose we will measure the difference in density of pneumococcal colonisation between groups, as density is likely related to transmission from person to person. Finally, we will perform additional functional tests of anti-pneumococcal immunoglobulin G at 10 and 18 months of age and determine whether immunoglobulin G concentration or function best correlate with later rates of pneumococcal acquisition. These data will be critical to international and national review of recommendations for PCV scheduling.
Technical Summary
Global control of pneumococcal disease is hampered by the cost of PCV. More than 20 countries are projected to 'transition' from GAVI vaccine subsidies in the next 5 years. Continuation of PCV programmes will require substantial increases in country expenditure on PCV.
Gambia introduced a three-dose PCV schedule without a booster dose (a '3+0' schedule), with large reductions in vaccine-type (VT) invasive pneumococcal disease (IPD) and pneumonia. Now that VT IPD is controlled, a cluster-randomised trial has begun comparing the ongoing use of the 3+0 schedule with transition to a two-dose schedule with a booster dose at 9 months of age (a '1+1' schedule). Theoretically, the 1+1 schedule will stimulate greater herd protection given its likely greater effect to prevent acquisition of pneumococcal bacteria. The ongoing study measures the effect of the two schedules on acquisition of pneumococcal carriage to 18 months of age as well as immunological measures. Despite this and other studies of the 1+1 schedule that are underway, significant gaps in knowledge remain, and none of the current studies will determine the duration of the effect of the booster dose to prevent acquisition of VT pneumococci, the effect of the booster dose on density of VT colonisation, nor whether anti-pneumococcal IgG concentration or function are associated with rates of VT acquisition.
The proposed study will extend randomised follow-up of 784 participants measuring VT acquisition with repeated nasopharyngeal specimens to 28 months of age, VT colonisation density at age 10 months by qPCR and pneumococcal microarray serotyping, and opsonophagocytic activity in additional participants to compare with the effect of IgG concentration on rates of acquisition.
Our findings will inform WHO policy on PCV scheduling, allow mechanistic interpretation of the trial results, and provide duration of protection and force-of-infection inputs into mathematical modeling of the booster dose effect.
Gambia introduced a three-dose PCV schedule without a booster dose (a '3+0' schedule), with large reductions in vaccine-type (VT) invasive pneumococcal disease (IPD) and pneumonia. Now that VT IPD is controlled, a cluster-randomised trial has begun comparing the ongoing use of the 3+0 schedule with transition to a two-dose schedule with a booster dose at 9 months of age (a '1+1' schedule). Theoretically, the 1+1 schedule will stimulate greater herd protection given its likely greater effect to prevent acquisition of pneumococcal bacteria. The ongoing study measures the effect of the two schedules on acquisition of pneumococcal carriage to 18 months of age as well as immunological measures. Despite this and other studies of the 1+1 schedule that are underway, significant gaps in knowledge remain, and none of the current studies will determine the duration of the effect of the booster dose to prevent acquisition of VT pneumococci, the effect of the booster dose on density of VT colonisation, nor whether anti-pneumococcal IgG concentration or function are associated with rates of VT acquisition.
The proposed study will extend randomised follow-up of 784 participants measuring VT acquisition with repeated nasopharyngeal specimens to 28 months of age, VT colonisation density at age 10 months by qPCR and pneumococcal microarray serotyping, and opsonophagocytic activity in additional participants to compare with the effect of IgG concentration on rates of acquisition.
Our findings will inform WHO policy on PCV scheduling, allow mechanistic interpretation of the trial results, and provide duration of protection and force-of-infection inputs into mathematical modeling of the booster dose effect.
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