An Aspiration to Radically Shorten Phase 3 Tuberculosis Vaccine Trials.

A new tuberculosis vaccine is a high priority. However, the classical development pathway is a major deterrent. Most tuberculosis cases arise within 2 years after Mycobacterium tuberculosis exposure, suggesting a 3-year trial period should be possible if sample size is large to maximize the number of early exposures. Increased sample size could be facilitated by working alongside optimized routine services for case ascertainment, with strategies for enhanced case detection and safety monitoring. Shortening enrolment could be achieved by simplifying screening criteria and procedures and strengthening site capacity. Together, these measures could enable radically shortened phase 3 tuberculosis vaccine trials.

A Phase IIa Controlled Human Malaria Infection and Immunogenicity Study of RTS,S/AS01E and RTS,S/AS01B Delayed Fractional Dose Regimens in Malaria-Naive Adults.

BACKGROUND: A previous RTS,S/AS01B vaccine challenge trial demonstrated that a 3-dose (0-1-7-month) regimen with a fractional third dose can produce high vaccine efficacy (VE) in adults challenged 3 weeks after vaccination. This study explored the VE of different delayed fractional dose regimens of adult and pediatric RTS,S/AS01 formulations. METHODS: A total of 130 participants were randomized into 5 groups. Four groups received 3 doses of RTS,S/AS01B or RTS,S/AS01E on a 0-1-7-month schedule, with the final 1 or 2 doses being fractional (one-fifth dose volume). One group received 1 full (month 0) and 1 fractional (month 7) dose of RTS,S/AS01E. Immunized and unvaccinated control participants underwent Plasmodium falciparum-infected mosquito challenge (controlled human malaria infection) 3 months after immunization, a timing chosen to potentially discriminate VEs between groups. RESULTS: The VE of 3-dose formulations ranged from 55% (95% confidence interval, 27%-72%) to 76% (48%-89%). Groups administered equivalent formulations of RTS,S/AS01E and RTS,S/AS01B demonstrated comparable VE. The 2-dose group demonstrated lower VE (29% [95% confidence interval, 6%-46%]). All regimens were well tolerated and immunogenic, with trends toward higher anti-circumsporozoite antibody titers in participants protected against infection. CONCLUSIONS: RTS,S/AS01E can provide VE comparable to an equivalent RTS,S/AS01B regimen in adults, suggesting a universal formulation may be considered. Results also suggest that the 2-dose regimen is inferior to the 3-dose regimens evaluated. CLINICAL TRIAL REGISTRATION: NCT03162614.

Building momentum for malaria vaccine research and development: key considerations.

To maintain momentum towards improved malaria control and elimination, a vaccine would be a key addition to the intervention toolkit. Two approaches are recommended: (1) promote the development and short to medium term deployment of first generation vaccine candidates and (2) support innovation and discovery to identify and develop highly effective, long-lasting and affordable next generation malaria vaccines.

The Path to Group A Streptococcus Vaccines: World Health Organization Research and Development Technology Roadmap and Preferred Product Characteristics.

Group A Streptococcus (GAS) infections result in a considerable underappreciated burden of acute and chronic disease globally. A 2018 World Health Assembly resolution calls for better control and prevention. Providing guidance on global health research needs is an important World Health Organization (WHO) activity, influencing prioritization of investments. Here, the role, status, and directions in GAS vaccines research are discussed. WHO preferred product characteristics and a research and development technology roadmap, briefly presented, offer an actionable framework for vaccine development to regulatory and policy decision making, availability, and use. GAS vaccines should be considered for global prevention of the range of clinical manifestations and associated antibiotic use. Impediments related to antigen diversity, safety concerns, and the difficulty to establish vaccine efficacy against rheumatic heart disease are discussed. Demonstration of vaccine efficacy against pharyngitis and skin infections constitutes a key near-term strategic goal. Investments and collaborative partnerships to diversify and advance vaccine candidates are needed.

Tuberculosis vaccines: Rising opportunities.

Johan Vekemans, Katherine O'Brien, and Jeremy Farrar discuss recent breakthroughs in the search for a highly effective tuberculosis vaccine.

Stillbirth With Group B Streptococcus Disease Worldwide: Systematic Review and Meta-analyses.

BACKGROUND: There are an estimated 2.6 million stillbirths each year, many of which are due to infections, especially in low- and middle-income contexts. This paper, the eighth in a series on the burden of group B streptococcal (GBS) disease, aims to estimate the percentage of stillbirths associated with GBS disease. METHODS: We conducted systematic literature reviews (PubMed/Medline, Embase, Literatura Latino-Americana e do Caribe em Ciências da Saúde, World Health Organization Library Information System, and Scopus) and sought unpublished data from investigator groups. Studies were included if they reported original data on stillbirths (predominantly ≥28 weeks' gestation or ≥1000 g, with GBS isolated from a sterile site) as a percentage of total stillbirths. We did meta-analyses to derive pooled estimates of the percentage of GBS-associated stillbirths, regionally and worldwide for recent datasets. RESULTS: We included 14 studies from any period, 5 with recent data (after 2000). There were no data from Asia. We estimated that 1% (95% confidence interval [CI], 0-2%) of all stillbirths in developed countries and 4% (95% CI, 2%-6%) in Africa were associated with GBS. CONCLUSIONS: GBS is likely an important cause of stillbirth, especially in Africa. However, data are limited in terms of geographic spread, with no data from Asia, and cases worldwide are probably underestimated due to incomplete case ascertainment. More data, using standardized, systematic methods, are critical, particularly from low- and middle-income contexts where the highest burden of stillbirths occurs. These data are essential to inform interventions, such as maternal GBS vaccination.

Group B Streptococcal Disease Worldwide for Pregnant Women, Stillbirths, and Children: Why, What, and How to Undertake Estimates?

Improving maternal, newborn, and child health is central to Sustainable Development Goal targets for 2030, requiring acceleration especially to prevent 5.6 million deaths around the time of birth. Infections contribute to this burden, but etiological data are limited. Group B Streptococcus (GBS) is an important perinatal pathogen, although previously focus has been primarily on liveborn children, especially early-onset disease. In this first of an 11-article supplement, we discuss the following: (1) Why estimate the worldwide burden of GBS disease? (2) What outcomes of GBS in pregnancy should be included? (3) What data and epidemiological parameters are required? (4) What methods and models can be used to transparently estimate this burden of GBS? (5) What are the challenges with available data? and (6) How can estimates address data gaps to better inform GBS interventions including maternal immunization? We review all available GBS data worldwide, including maternal GBS colonization, risk of neonatal disease (with/without intrapartum antibiotic prophylaxis), maternal GBS disease, neonatal/infant GBS disease, and subsequent impairment, plus GBS-associated stillbirth, preterm birth, and neonatal encephalopathy. We summarize our methods for searches, meta-analyses, and modeling including a compartmental model. Our approach is consistent with the World Health Organization (WHO) Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER), published in The Lancet and the Public Library of Science (PLoS). We aim to address priority epidemiological gaps highlighted by WHO to inform potential maternal vaccination.

Intrapartum Antibiotic Chemoprophylaxis Policies for the Prevention of Group B Streptococcal Disease Worldwide: Systematic Review.

BACKGROUND: Intrapartum antibiotic chemoprophylaxis (IAP) prevents most early-onset group B streptococcal (GBS) disease. However, there is no description of how IAP is used around the world. This article is the sixth in a series estimating the burden of GBS disease. Here we aimed to review GBS screening policies and IAP implementation worldwide. METHODS: We identified data through (1) systematic literature reviews (PubMed/Medline, Embase, Literature in the Health Sciences in Latin America and the Caribbean [LILACS], World Health Organization library database [WHOLIS], and Scopus) and unpublished data from professional societies and (2) an online survey and searches of policies from medical societies and professionals. We included data on whether an IAP policy was in use, and if so whether it was based on microbiological or clinical risk factors and how these were applied, as well as the estimated coverage (percentage of women receiving IAP where indicated). RESULTS: We received policy information from 95 of 195 (49%) countries. Of these, 60 of 95 (63%) had an IAP policy; 35 of 60 (58%) used microbiological screening, 25 of 60 (42%) used clinical risk factors. Two of 15 (13%) low-income, 4 of 16 (25%) lower-middle-income, 14 of 20 (70%) upper-middle-income, and 40 of 44 (91%) high-income countries had any IAP policy. The remaining 35 of 95 (37%) had no national policy (25/33 from low-income and lower-middle-income countries). Coverage varied considerably; for microbiological screening, median coverage was 80% (range, 20%-95%); for clinical risk factor-based screening, coverage was 29% (range, 10%-50%). Although there were differences in the microbiological screening methods employed, the individual clinical risk factors used were similar. CONCLUSIONS: There is considerable heterogeneity in IAP screening policies and coverage worldwide. Alternative global strategies, such as maternal vaccination, are needed to enhance the scope of global prevention of GBS disease.

Risk of Early-Onset Neonatal Group B Streptococcal Disease With Maternal Colonization Worldwide: Systematic Review and Meta-analyses.

BACKGROUND: Early-onset group B streptococcal disease (EOGBS) occurs in neonates (days 0-6) born to pregnant women who are rectovaginally colonized with group B Streptococcus (GBS), but the risk of EOGBS from vertical transmission has not been systematically reviewed. This article, the seventh in a series on the burden of GBS disease, aims to estimate this risk and how it varies with coverage of intrapartum antibiotic prophylaxis (IAP), used to reduce the incidence of EOGBS. METHODS: We conducted systematic reviews (Pubmed/Medline, Embase, Latin American and Caribbean Health Sciences Literature (LILACS), World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data from investigator groups on maternal GBS colonization and neonatal outcomes. We included articles with ≥200 GBS colonized pregnant women that reported IAP coverage. We did meta-analyses to determine pooled estimates of risk of EOGBS, and examined the association in risk of EOGBS with IAP coverage. RESULTS: We identified 30 articles including 20328 GBS-colonized pregnant women for inclusion. The risk of EOGBS in settings without an IAP policy was 1.1% (95% confidence interval [CI], .6%-1.5%). As IAP increased, the risk of EOGBS decreased, with a linear association. Based on linear regression, the risk of EOGBS in settings with 80% IAP coverage was predicted to be 0.3% (95% CI, 0-.9). CONCLUSIONS: The risk of EOGBS among GBS-colonized pregnant women, from this first systematic review, is consistent with previous estimates from single studies (1%-2%). Increasing IAP coverage was linearly associated with decreased risk of EOGBS disease.

Maternal Colonization With Group B Streptococcus and Serotype Distribution Worldwide: Systematic Review and Meta-analyses.

BACKGROUND: Maternal rectovaginal colonization with group B Streptococcus (GBS) is the most common pathway for GBS disease in mother, fetus, and newborn. This article, the second in a series estimating the burden of GBS, aims to determine the prevalence and serotype distribution of GBS colonizing pregnant women worldwide. METHODS: We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus), organized Chinese language searches, and sought unpublished data from investigator groups. We applied broad inclusion criteria to maximize data inputs, particularly from low- and middle-income contexts, and then applied new meta-analyses to adjust for studies with less-sensitive sampling and laboratory techniques. We undertook meta-analyses to derive pooled estimates of maternal GBS colonization prevalence at national and regional levels. RESULTS: The dataset regarding colonization included 390 articles, 85 countries, and a total of 299924 pregnant women. Our adjusted estimate for maternal GBS colonization worldwide was 18% (95% confidence interval [CI], 17%-19%), with regional variation (11%-35%), and lower prevalence in Southern Asia (12.5% [95% CI, 10%-15%]) and Eastern Asia (11% [95% CI, 10%-12%]). Bacterial serotypes I-V account for 98% of identified colonizing GBS isolates worldwide. Serotype III, associated with invasive disease, accounts for 25% (95% CI, 23%-28%), but is less frequent in some South American and Asian countries. Serotypes VI-IX are more common in Asia. CONCLUSIONS: GBS colonizes pregnant women worldwide, but prevalence and serotype distribution vary, even after adjusting for laboratory methods. Lower GBS maternal colonization prevalence, with less serotype III, may help to explain lower GBS disease incidence in regions such as Asia. High prevalence worldwide, and more serotype data, are relevant to prevention efforts.

Infant Group B Streptococcal Disease Incidence and Serotypes Worldwide: Systematic Review and Meta-analyses.

BACKGROUND: Group B Streptococcus (GBS) remains a leading cause of neonatal sepsis in high-income contexts, despite declines due to intrapartum antibiotic prophylaxis (IAP). Recent evidence suggests higher incidence in Africa, where IAP is rare. We investigated the global incidence of infant invasive GBS disease and the associated serotypes, updating previous estimates. METHODS: We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data regarding invasive GBS disease in infants aged 0-89 days. We conducted random-effects meta-analyses of incidence, case fatality risk (CFR), and serotype prevalence. RESULTS: We identified 135 studies with data on incidence (n = 90), CFR (n = 64), or serotype (n = 45). The pooled incidence of invasive GBS disease in infants was 0.49 per 1000 live births (95% confidence interval [CI], .43-.56), and was highest in Africa (1.12) and lowest in Asia (0.30). Early-onset disease incidence was 0.41 (95% CI, .36-.47); late-onset disease incidence was 0.26 (95% CI, .21-.30). CFR was 8.4% (95% CI, 6.6%-10.2%). Serotype III (61.5%) dominated, with 97% of cases caused by serotypes Ia, Ib, II, III, and V. CONCLUSIONS: The incidence of infant GBS disease remains high in some regions, particularly Africa. We likely underestimated incidence in some contexts, due to limitations in case ascertainment and specimen collection and processing. Burden in Asia requires further investigation.

Preterm Birth Associated With Group B Streptococcus Maternal Colonization Worldwide: Systematic Review and Meta-analyses.

BACKGROUND: Preterm birth complications are the leading cause of deaths among children <5 years of age. Studies have suggested that group B Streptococcus (GBS) maternal rectovaginal colonization during pregnancy may be a risk factor for preterm delivery. This article is the fifth of 11 in a series. We aimed to assess the association between GBS maternal colonization and preterm birth in order to inform estimates of the burden of GBS. METHODS: We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data from investigator groups on the association of preterm birth (<37 weeks' gestation) and maternal GBS colonization (GBS isolation from vaginal, cervical, and/or rectal swabs; with separate subanalysis on GBS bacteriuria). We did meta-analyses to derive pooled estimates of the risk and odds ratios (according to study design), with sensitivity analyses to investigate potential biases. RESULTS: We identified 45 studies for inclusion. We estimated the risk ratio (RR) for preterm birth with maternal GBS colonization to be 1.21 (95% confidence interval [CI], .99-1.48; P = .061) in cohort and cross-sectional studies, and the odds ratio to be 1.85 (95% CI, 1.24-2.77; P = .003) in case-control studies. Preterm birth was associated with GBS bacteriuria in cohort studies (RR, 1.98 [95% CI, 1.45-2.69]; P < .001). CONCLUSIONS: From this review, there is evidence to suggest that preterm birth is associated with maternal GBS colonization, especially where there is evidence of ascending infection (bacteriuria). Several biases reduce the chance of detecting an effect. Equally, however, results, including evidence for the association, may be due to confounding, which is rarely addressed in studies. Assessment of any effect on preterm delivery should be included in future maternal GBS vaccine trials.

Maternal Disease With Group B Streptococcus and Serotype Distribution Worldwide: Systematic Review and Meta-analyses.

BACKGROUND: Infections such as group B Streptococcus (GBS) are an important cause of maternal sepsis, yet limited data on epidemiology exist. This article, the third of 11, estimates the incidence of maternal GBS disease worldwide. METHODS: We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data on invasive GBS disease in women pregnant or within 42 days postpartum. We undertook meta-analyses to derive pooled estimates of the incidence of maternal GBS disease. We examined maternal and perinatal outcomes and GBS serotypes. RESULTS: Fifteen studies and 1 unpublished dataset were identified, all from United Nations-defined developed regions. From a single study with pregnancies as the denominator, the incidence of maternal GBS disease was 0.38 (95% confidence interval [CI], .28-.48) per 1000 pregnancies. From 3 studies reporting cases by the number of maternities (pregnancies resulting in live/still birth), the incidence was 0.23 (95% CI, .09-.37). Five studies reported serotypes, with Ia being the most common (31%). Most maternal GBS disease was detected at or after delivery. CONCLUSIONS: Incidence data on maternal GBS disease in developing regions are lacking. In developed regions the incidence is low, as are the sequelae for the mother, but the risk to the fetus and newborn is substantial. The timing of GBS disease suggests that a maternal vaccine given in the late second or early third trimester of pregnancy would prevent most maternal cases.

Neonatal Encephalopathy With Group B Streptococcal Disease Worldwide: Systematic Review, Investigator Group Datasets, and Meta-analysis.

BACKGROUND: Neonatal encephalopathy (NE) is a leading cause of child mortality and longer-term impairment. Infection can sensitize the newborn brain to injury; however, the role of group B streptococcal (GBS) disease has not been reviewed. This paper is the ninth in an 11-article series estimating the burden of GBS disease; here we aim to assess the proportion of GBS in NE cases. METHODS: We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data from investigator groups reporting GBS-associated NE. Meta-analyses estimated the proportion of GBS disease in NE and mortality risk. UK population-level data estimated the incidence of GBS-associated NE. RESULTS: Four published and 25 unpublished datasets were identified from 13 countries (N = 10436). The proportion of NE associated with GBS was 0.58% (95% confidence interval [CI], 0.18%-.98%). Mortality was significantly increased in GBS-associated NE vs NE alone (risk ratio, 2.07 [95% CI, 1.47-2.91]). This equates to a UK incidence of GBS-associated NE of 0.019 per 1000 live births. CONCLUSIONS: The consistent increased proportion of GBS disease in NE and significant increased risk of mortality provides evidence that GBS infection contributes to NE. Increased information regarding this and other organisms is important to inform interventions, especially in low- and middle-resource contexts.

Estimates of the Burden of Group B Streptococcal Disease Worldwide for Pregnant Women, Stillbirths, and Children.

BACKGROUND: We aimed to provide the first comprehensive estimates of the burden of group B Streptococcus (GBS), including invasive disease in pregnant and postpartum women, fetal infection/stillbirth, and infants. Intrapartum antibiotic prophylaxis is the current mainstay of prevention, reducing early-onset infant disease in high-income contexts. Maternal GBS vaccines are in development. METHODS: For 2015 live births, we used a compartmental model to estimate (1) exposure to maternal GBS colonization, (2) cases of infant invasive GBS disease, (3) deaths, and (4) disabilities. We applied incidence or prevalence data to estimate cases of maternal and fetal infection/stillbirth, and infants with invasive GBS disease presenting with neonatal encephalopathy. We applied risk ratios to estimate numbers of preterm births attributable to GBS. Uncertainty was also estimated. RESULTS: Worldwide in 2015, we estimated 205000 (uncertainty range [UR], 101000-327000) infants with early-onset disease and 114000 (UR, 44000-326000) with late-onset disease, of whom a minimum of 7000 (UR, 0-19000) presented with neonatal encephalopathy. There were 90000 (UR, 36000-169000) deaths in infants <3 months age, and, at least 10000 (UR, 3000-27000) children with disability each year. There were 33000 (UR, 13000-52000) cases of invasive GBS disease in pregnant or postpartum women, and 57000 (UR, 12000-104000) fetal infections/stillbirths. Up to 3.5 million preterm births may be attributable to GBS. Africa accounted for 54% of estimated cases and 65% of all fetal/infant deaths. A maternal vaccine with 80% efficacy and 90% coverage could prevent 107000 (UR, 20000-198000) stillbirths and infant deaths. CONCLUSIONS: Our conservative estimates suggest that GBS is a leading contributor to adverse maternal and newborn outcomes, with at least 409000 (UR, 144000-573000) maternal/fetal/infant cases and 147000 (UR, 47000-273000) stillbirths and infant deaths annually. An effective GBS vaccine could reduce disease in the mother, the fetus, and the infant.

Neurodevelopmental Impairment in Children After Group B Streptococcal Disease Worldwide: Systematic Review and Meta-analyses.

BACKGROUND: Survivors of infant group B streptococcal (GBS) disease are at risk of neurodevelopmental impairment (NDI), a burden not previously systematically quantified. This is the 10th of 11 articles estimating the burden of GBS disease. Here we aimed to estimate NDI in survivors of infant GBS disease. METHODS: We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data on the risk of NDI after invasive GBS disease in infants <90 days of age. We did meta-analyses to derive pooled estimates of the percentage of infants with NDI following GBS meningitis. RESULTS: We identified 6127 studies, of which 18 met eligibility criteria, all from middle- or high-income contexts. All 18 studies followed up survivors of GBS meningitis; only 5 of these studies also followed up survivors of GBS sepsis and were too few to pool in a meta-analysis. Of meningitis survivors, 32% (95% CI, 25%-38%) had NDI at 18 months of follow-up, including 18% (95% CI, 13%-22%) with moderate to severe NDI. CONCLUSIONS: GBS meningitis is an important risk factor for moderate to severe NDI, affecting around 1 in 5 survivors. However, data are limited, and we were unable to estimate NDI after GBS sepsis. Comparability of studies is difficult due to methodological differences including variability in timing of clinical reviews and assessment tools. Follow-up of clinical cases and standardization of methods are essential to fully quantify the total burden of NDI associated with GBS disease, and inform program priorities.

Safety and High Level Efficacy of the Combination Malaria Vaccine Regimen of RTS,S/AS01B With Chimpanzee Adenovirus 63 and Modified Vaccinia Ankara Vectored Vaccines Expressing ME-TRAP.

BACKGROUND: The need for a highly efficacious vaccine against Plasmodium falciparum remains pressing. In this controlled human malaria infection (CHMI) study, we assessed the safety, efficacy and immunogenicity of a schedule combining 2 distinct vaccine types in a staggered immunization regimen: one inducing high-titer antibodies to circumsporozoite protein (RTS,S/AS01B) and the other inducing potent T-cell responses to thrombospondin-related adhesion protein (TRAP) by using a viral vector. METHOD: Thirty-seven healthy malaria-naive adults were vaccinated with either a chimpanzee adenovirus 63 and modified vaccinia virus Ankara-vectored vaccine expressing a multiepitope string fused to TRAP and 3 doses of RTS,S/AS01B (group 1; n = 20) or 3 doses of RTS,S/AS01B alone (group 2; n = 17). CHMI was delivered by mosquito bites to 33 vaccinated subjects at week 12 after the first vaccination and to 6 unvaccinated controls. RESULTS: No suspected unexpected serious adverse reactions or severe adverse events related to vaccination were reported. Protective vaccine efficacy was observed in 14 of 17 subjects (82.4%) in group 1 and 12 of 16 subjects (75%) in group 2. All control subjects received a diagnosis of blood-stage malaria parasite infection. Both vaccination regimens were immunogenic. Fourteen protected subjects underwent repeat CHMI 6 months after initial CHMI; 7 of 8 (87.5%) in group 1 and 5 of 6 (83.3%) in group 2 remained protected. CONCLUSIONS: The high level of sterile efficacy observed in this trial is encouraging for further evaluation of combination approaches using these vaccine types. CLINICAL TRIALS REGISTRATION: NCT01883609.

Demonstration of the Blood-Stage Plasmodium falciparum Controlled Human Malaria Infection Model to Assess Efficacy of the P. falciparum Apical Membrane Antigen 1 Vaccine, FMP2.1/AS01.

BACKGROUND: Models of controlled human malaria infection (CHMI) initiated by mosquito bite have been widely used to assess efficacy of preerythrocytic vaccine candidates in small proof-of-concept phase 2a clinical trials. Efficacy testing of blood-stage malaria parasite vaccines, however, has generally relied on larger-scale phase 2b field trials in malaria-endemic populations. We report the use of a blood-stage P. falciparum CHMI model to assess blood-stage vaccine candidates, using their impact on the parasite multiplication rate (PMR) as the primary efficacy end point. METHODS: Fifteen healthy United Kingdom adult volunteers were vaccinated with FMP2.1, a protein vaccine that is based on the 3D7 clone sequence of apical membrane antigen 1 (AMA1) and formulated in Adjuvant System 01 (AS01). Twelve vaccinees and 15 infectivity controls subsequently underwent blood-stage CHMI. Parasitemia was monitored by quantitative real-time polymerase chain reaction (PCR) analysis, and PMR was modeled from these data. RESULTS: FMP2.1/AS01 elicited anti-AMA1 T-cell and serum antibody responses. Analysis of purified immunoglobulin G showed functional growth inhibitory activity against P. falciparum in vitro. There were no vaccine- or CHMI-related safety concerns. All volunteers developed blood-stage parasitemia, with no impact of the vaccine on PMR. CONCLUSIONS: FMP2.1/AS01 demonstrated no efficacy after blood-stage CHMI. However, the model induced highly reproducible infection in all volunteers and will accelerate proof-of-concept testing of future blood-stage vaccine candidates. CLINICAL TRIALS REGISTRATION: NCT02044198.

Fractional Third and Fourth Dose of RTS,S/AS01 Malaria Candidate Vaccine: A Phase 2a Controlled Human Malaria Parasite Infection and Immunogenicity Study.

BACKGROUND: Three full doses of RTS,S/AS01 malaria vaccine provides partial protection against controlled human malaria parasite infection (CHMI) and natural exposure. Immunization regimens, including a delayed fractional third dose, were assessed for potential increased protection against malaria and immunologic responses. METHODS: In a phase 2a, controlled, open-label, study of healthy malaria-naive adults, 16 subjects vaccinated with a 0-, 1-, and 2-month full-dose regimen (012M) and 30 subjects who received a 0-, 1-, and 7-month regimen, including a fractional third dose (Fx017M), underwent CHMI 3 weeks after the last dose. Plasmablast heavy and light chain immunoglobulin messenger RNA sequencing and antibody avidity were evaluated. Protection against repeat CHMI was evaluated after 8 months. RESULTS: A total of 26 of 30 subjects in the Fx017M group (vaccine efficacy [VE], 86.7% [95% confidence interval [CI], 66.8%-94.6%]; P < .0001) and 10 of 16 in the 012M group (VE, 62.5% [95% CI, 29.4%-80.1%]; P = .0009) were protected against infection, and protection differed between schedules (P = .040, by the log rank test). The fractional dose boosting increased antibody somatic hypermutation and avidity and sustained high protection upon rechallenge. DISCUSSIONS: A delayed third fractional vaccine dose improved immunogenicity and protection against infection. Optimization of the RTS,S/AS01 immunization regimen may lead to improved approaches against malaria. CLINICAL TRIALS REGISTRATION: NCT01857869.