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Using National Immunization Survey Child and Teen (2008-2017), we associated state vaccination requirements with hepatitis A (Hep A) vaccination rates in children and adolescents. States with school entry or both childcare and school entry requirements were associated with 35%-40% higher Hep A vaccination rates, compared with states without such requirements.

Background: Older adults are at risk of pneumococcal disease and associated morbidity and mortality. This phase 3 study (V114-020) assessed lot-to-lot consistency across safety and immunogenicity outcomes for V114, a 15-valent pneumococcal conjugate vaccine (PCV), in healthy adults aged ≥ 50 years. Methods: Adults were randomized in a 3:3:3:1 ratio to receive a single dose of one of three lots of V114 or 13-valent PCV (PCV13), stratified by age (50–64 years, 65–74 years, and ≥ 75 years). Serotype-specific opsonophagocytic activity (OPA) and immunoglobulin G (IgG) antibodies were evaluated at baseline (Day 1) and 30 days post-vaccination. Non-serious and serious adverse events (AEs) were evaluated post-vaccination through 14 days and Month 6, respectively. Results: Of 2340 participants enrolled, 2282 (97.5%) completed the study. Proportions of participants experiencing ≥ 1 AE were 81.0%, 77.4%, and 78.0% for V114 lots 1, 2, and 3, respectively. Comparison of V114 combined lots with PCV13 showed that proportions of participants experiencing AEs, solicited AEs, and serious AEs were comparable for both vaccines, with the exception of injection-site pain (more frequently reported with V114). OPA geometric mean titers (GMTs) and IgG geometric mean concentrations (GMCs) at 30 days post-vaccination were comparable across V114 lots, and all lots met predefined equivalence criteria for all 15 vaccine serotypes (lower and upper limits of the 95% confidence intervals of serotype-specific OPA GMT ratios for all possible pairwise comparisons across the three lots were within the equivalence margin of 0.5–2.0). Serotype-specific OPA GMTs and IgG GMCs were comparable in the V114 combined lots and PCV13 groups for the 13 shared serotypes and higher in the V114 group for serotypes unique to V114 (22F and 33F). Conclusions: V114 is well tolerated with a consistent safety profile and immune response across manufacturing lots. Clinical trials registration: NCT03950856 (www.clinicaltrials.gov); 2018-004266-33 (EudraCT).

OBJECTIVES To evaluate safety and immunogenicity of V114 (15-valent pneumococcal conjugate vaccine [PCV] containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9 V, 14, 18C, 19A, 19F, 22F, 23F, and 33F), followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) 8 weeks later, in adults living with HIV. DESIGN In this phase 3 study (V114-018; NCT03480802), pneumococcal vaccine-naive adults with HIV (CD4+ count ≥50 cells/μl, plasma HIV RNA

Gamma irradiation (GI) is included in the CDC guidance on inactivation procedures to render a group of select agents and toxins nonviable. The Ebola virus falls within this group because it potentially poses a severe threat to public health and safety. To evaluate the impact of GI at a target dose of 50 kGy on neutralizing antibody titers induced by the rVSVΔG-ZEBOV-GP vaccine (V920), we constructed a panel of 48 paired human serum samples (GI-treated versus non–GI-treated) from healthy participants selected from a phase 3 study of V920 (study V920-012; NCT02503202). Neutralizing antibody titers were determined using a validated plaque-reduction neutralization test. GI of sera from V920 recipients was associated with approximately 20% reduction in postvaccination neutralizing antibody titers. GI was not associated with any change in pre-vaccination neutralizing antibody titers.

The recombinant vesicular stomatitis virus - Zaire Ebola virus envelope glycoprotein (rVSVΔG-ZEBOV-GP) vaccine is a live recombinant vesicular stomatitis virus (VSV) where the VSV G protein is replaced with ZEBOV-GP. To better understand the immune response after receiving the rVSVΔG-ZEBOV-GP vaccine, the current analyses evaluated different definitions of seroresponse that differentiate vaccine and placebo recipients enrolled in a placebo-controlled clinical trial (PREVAIL; NCT02344407) in which a subset of the study participants had elevated baseline titers. Alternative values for serostatus cutoff (SSCO; 200-500 EU/mL) and/or fold rise (two- to five-fold) were applied to compare their ability to distinguish between participants receiving rVSVΔG-ZEBOV-GP or placebo. The results indicate that an SSCO of 200 EU/mL can be used to define seropositivity at baseline (i.e. pre-vaccination). The use of dual criteria of the same SSCO (200 EU/mL) together with a two-fold rise in antibody level from baseline provided the definition of seroresponse that maximized the statistical significance between vaccine recipients and placebo recipients post-vaccination. Clinical trial registration: NCT02344407.

ERVEBO®, a live recombinant vesicular stomatitis virus (VSV) vaccine containing the Zaire ebolavirus glycoprotein (GP) in place of the VSV GP (rVSVΔG-ZEBOV-GP), was advanced through clinical development by MerckCo., Inc., Rahway, NJ, USA in collaboration with multiple partners to prevent Ebola virus disease (EVD) and has been approved for human use in several countries.We evaluated data from three Phase 2/3 clinical trials conducted in Liberia (PREVAIL), Guinea (FLW), and Sierra Leone (STRIVE) during the 2013-2016 West African EVD outbreak to assess immune responses using validated assays. We performed a post hoc analysis of the association of vaccine response with sex, age (18-50 yrs50 yrs), and baseline (BL) GP-enzyme-linked immunosorbent assay (ELISA) titer (200≥200 EU/mL), including individual study (PREVAIL, FLW, or STRIVE) data and pooled data from all 3 studies. The endpoints were total IgG antibody response (EU/mL) measured by the GP-ELISA and neutralizing antibody response measured by the plaque reduction neutralization test (PRNT) to rVSVΔG-ZEBOV-GP at Days 28, 180, and 365 postvaccination.In the overall pooled population, in all subgroups, and in each trial independently, GP-ELISA and PRNT geometric mean titers increased from BL, generally peaking at Day 28 and persisting through Day 365. Immune responses were greater in women and participants with BL GP-ELISA ≥ 200 EU/mL, but did not differ across age groups.These data demonstrate that rVSVΔG-ZEBOV-GP elicits a robust and durable immune response through 12 months postvaccination in participants regardless of age, sex, or BL GP-ELISA titer. The higher immune responses observed in women and participants with pre-existing immunity are consistent with those described previously and for other vaccines. Trials were registered as follows: PREVAIL: ClinicalTrials.gov NCT02344407; FLW: Pan African Clinical Trials Registry PACTR201503001057193; STRIVE: ClinicalTrials.gov NCT02378753. Protocols V920-009, 011, and 018.

The requirements to gain licensure and manufacture a vaccine for human use are multifaceted, costly, and time-consuming. Despite the expenditure and challenges, preventative vaccines are considered one of the most cost-effective and efficient means to contain outbreaks and prevent epidemics. In the face of the 2013–2016 Ebolavirus disease (EVD) outbreak, which was the largest EVD outbreak to date and the third Public Health Emergency of International Concern in history, numerous partners from the public and private sectors combined efforts and resources to develop an investigational Zaire ebolavirus (EBOV) vaccine candidate (rVSVΔG–ZEBOV–GP) as quickly as possible. The rVSVΔG–ZEBOV–GP vaccine was approved as ERVEBO™ by the EMA and FDA in late 2019 after five years of clinical development. This chapter describes the development program of this EBOV vaccine.

Background This double-blind study assessed immunogenicity, lot consistency, and safety of recombinant vesicular stomatitis virus-Zaire Ebola virus envelope glycoprotein vaccine (rVSVΔG-ZEBOV-GP). Methods Healthy adults (N = 1197) were randomized 2:2:2:2:1 to receive 1 of 3 consistency lots of rVSVΔG-ZEBOV-GP (2 × 107 plaque-forming units [pfu]), high-dose 1 × 108 pfu, or placebo. Antibody responses pre-/postvaccination (28 days, 6 months; in a subset [n = 566], months 12, 18, and 24) were measured. post hoc analysis of risk factors associated with arthritis following vaccination was performed. Results ZEBOV-GP enzyme-linked immunosorbent assay (ELISA) geometric mean titers (GMTs) increased postvaccination in all rVSVΔG-ZEBOV-GP groups by 28 days (>58-fold) and persisted through 24 months. The 3 manufacturing lots demonstrated equivalent immunogenicity at 28 days. Neutralizing antibody GMTs increased by 28 days in all rVSVΔG-ZEBOV-GP groups, peaking at 18 months with no decrease through 24 months. At 28 days, ≥94% of vaccine recipients seroresponded (ZEBOV-GP ELISA, ≥2-fold increase, titer ≥200 EU/mL), with responses persisting at 24 months in ≥91%. Female sex and a history of arthritis were identified as potential risk factors for the development of arthritis postvaccination. Conclusions Immune responses to rVSVΔG-ZEBOV-GP persisted to 24 months. Immunogenicity and safety results support continued rVSVΔG-ZEBOV-GP development. Clinical Trials Registration NCT02503202., Immune responses to rVSVΔG-ZEBOV-GP, measured by ZEBOV-GP immunoglobulin G enzyme-linked immunosorbent assay and plaque reduction neutralization test, were robust and persisted up to 24 months. Together with the favorable safety profile, the immunogenicity results support continued rVSVΔG-ZEBOV-GP development.

VAQTA™ (Hepatitis A Vaccine, inactivated [HAVi]; Merck & Co., Inc., Kenilworth, NJ, USA) is currently licensed for prevention of disease caused by hepatitis A virus in persons ≥12 months of age. This report summarizes statistical models developed to evaluate the long-term persistence and duration of detectable hepatitis A antibody (total antibody levels with no distinction on class) after receipt of HAVi in healthy children and adolescents (V251-023 and V251-035) and in healthy adults (V251-034). The statistical models presented, conducted separately for each of the three studies, are based on models that have been used in the literature to estimate the duration of antibody to protect against human papillomavirus (HPV) disease. In the absence of observed study data on hepatitis A antibody persistence for vaccine recipients over several decades, an extrapolation from a kinetic model of antibody decay was used to estimate the duration of detectable antibody. Extrapolation of observed antibody titers from postvaccination, Year 2.5–3.5, Year 5–6, and Year 10 in 165 children and adolescents who received HAVi at Day 0 and Week 24 in V251-023 suggests that detectable levels of antibody may persist after the second dose for many years. This model suggests that 25 to 50 years Postdose 1 in a two-dose series of HAVi, 99.4% of the study population will have detectable levels of hepatitis A antibody.

Background The single-dose live attenuated vaccine CVD 103-HgR protects against experimental Vibrio cholerae infection in cholera-naive adults for at least 6 months after vaccination. While vaccine-induced vibriocidal seroconversion is associated with protection, vibriocidal titers decline rapidly from their peak 1–2 weeks after vaccination. Although vaccine-induced memory B cells (MBCs) might mediate sustained protection in individuals without detectable circulating antibodies, it is unknown whether oral cholera vaccination induces a MBC response. Methods In a study that enrolled North American adults, we measured lipopolysaccharide (LPS)- and cholera toxin (CtxB)-specific MBC responses to PXVX0200 (derived from the CVD 103-HgR strain) and assessed stool volumes following experimental Vibrio cholerae infection. We then evaluated the association between vaccine-induced MBC responses and protection against cholera. Results There was a significant increase in % CT-specific IgG, % LPS-specific IgG, and % LPS-specific IgA MBCs which persisted 180 days after vaccination as well as a significant association between vaccine-induced increase in % LPS-specific IgA MBCs and lower post-challenge stool volume (r = −0.56, p Discussion Oral cholera vaccination induces antigen-specific MBC responses, and the anamnestic LPS-specific responses may contribute to long-term protection and provide correlates of the duration of vaccine-induced protection. Clinical trials registration: NCT01895855.

The attenuated recombinant Vibrio cholerae O1 vaccine strain CVD 103-HgR, re-developed as PXVX0200, elicits a rapid serum vibriocidal antibody (SVA) response and protects against cholera diarrhea in volunteer challenge studies. We performed a phase 3, placebo controlled, double blind, multi-center study to further assess the safety, immunogenicity, and lot-to-lot consistency of PXVX0200. Adult volunteers 18–45 years of age were randomized 8:1 to receive a single dose of 1 × 109 CFU of PXVX0200 from three production lots or saline placebo. Immunogenicity endpoints included SVA and anti-cholera toxin (CT) antibody levels on days 1, 11, 29, 91 and 181. Safety was assessed by comparing solicited signs and symptoms on days 1–8, unsolicited adverse events through day 29 and serious adverse events through day 181. A total of 3146 participants were enrolled, including 2795 vaccine and 351 placebo recipients. The SVA seroconversion rates at day 11 were 94% and 4% in the PXVX0200 and placebo recipients, respectively (P Clinical Trials Registration: Clinicaltrials.gov NCT02094586.

The 2014-2016 Ebola outbreak caused over 28,000 cases and 11,000 deaths. Merck & Co. Inc., Kenilworth, NJ USA and NewLink Genetics are working with private and public partners to develop and license an Ebola vaccine that was evaluated extensively during the outbreak. The vaccine referred to as V920 is a recombinant vesicular stomatitis virus (rVSV) in which the VSV-G envelope glycoprotein (GP) is completely replaced by the Zaire ebolavirus GP (rVSVΔG-ZEBOV-GP). Eight Phase I and four Phase II/III clinical trials enrolling approximately 17,000 subjects were conducted in parallel to the outbreak to assess the safety, immunogenicity, and/or efficacy of V920. Immunogenicity data demonstrate that anti-GP antibodies are generally detectable by ELISA by 14days postvaccination with up to 100% seroconversion observed by 28days post dose. In addition, the results of a ring vaccination trial conducted by the WHO and their partners in Guinea suggest robust vaccine efficacy within 10days of receipt of a single dose of vaccine. The vaccine is generally well-tolerated when administered to healthy, non-pregnant adults. The development of this vaccine candidate in the context of this unprecedented epidemic has involved the close cooperation of large number of international partners and highlights what we as a public health community can accomplish when working together towards a common goal. Study identification: V920-001 to V920-012. CLINICALTRIALS.GOV identifiers: NCT02269423; NCT02280408; NCT02374385; NCT02314923; NCT02287480; NCT02283099; NCT02296983; NCT02344407; NCT02378753; NCT02503202.

Background. No licensed cholera vaccine is presently available in the United States. Cholera vaccines available in other countries require 2 spaced doses. A single-dose cholera vaccine that can rapidly protect short-notice travelers to high-risk areas and help control explosive outbreaks where logistics render 2-dose immunization regimens impractical would be a major advance. PXVX0200, based on live attenuated Vibrio cholerae O1 classical Inaba vaccine strain CVD 103-HgR, elicits seroconversion of vibriocidal antibodies (a correlate of protection) within 10 days of a single oral dose. We investigated the protection conferred by this vaccine in a human cholera challenge model. Methods. Consenting healthy adult volunteers, 18–45 years old, were randomly allocated 1:1 to receive 1 oral dose of vaccine (approximately 5 × 108 colony-forming units [CFU]) or placebo in double-blind fashion. Volunteers ingested approximately 1 × 105 CFU of wild-type V. cholerae O1 El Tor Inaba strain N16961 10 days or 3 months after vaccination and were observed on an inpatient research ward for stool output measurement and management of hydration. Results. The vaccine was well tolerated, with no difference in adverse event frequency among 95 vaccinees vs 102 placebo recipients. The primary endpoint, moderate (≥3.0 L) to severe (≥5.0 L) diarrheal purge, occurred in 39 of 66 (59.1%) placebo controls but only 2 of 35 (5.7%) vaccinees at 10 days (vaccine efficacy, 90.3%; P < .0001) and 4 of 33 (12.1%) vaccinees at 3 months (vaccine efficacy, 79.5%; P < .0001). Conclusions. The significant vaccine efficacy documented 10 days and 3 months after 1 oral dose of PXVX0200 supports further development as a single-dose cholera vaccine. Clinical Trials Registration. {"type":"clinical-trial","attrs":{"text":"NCT01895855","term_id":"NCT01895855"}}NCT01895855

Background Widespread Hepatitis A (Hep A) outbreaks in the United States (US) have raised the importance of vaccination. Vaccination requirements for childcare and school entry could be an effective strategy to ensure compliance to recommended vaccination schedule. We assessed the association between state childcare and school entry requirements for Hep A vaccination and vaccine coverage rate among children and adolescents in the US. Methods We conducted a cross-sectional cohort study using National Immunization Survey-Child and Teen dataset between 2008 and 2017. We included children aged 19–35 months and adolescents aged 13–17 years residing in states with childcare entry requirement only (C); school entry requirement only (S); childcare AND school entry requirement (C+S); and neither of requirements in place in the survey year (Control). We developed a multivariate logistic regression model adjusting for demographics, survey year, state’s CDC vaccination recommendation status, stringency of requirement, and history of Hep A outbreak, accounting for the survey design. Results We included 150,653 children and 119,265 adolescents in the analysis. Vaccination initiation rate was 53.9% and 72.6% (C), 48.3% and 74.9% (S), 48.2% and 83.9% (C+S) in pre- and post-requirement periods, respectively. In multivariate analysis, all state requirements were associated with higher Hep A vaccination initiation compared to control states (C: odds ratio 1.51, 95% confidence interval 1.37–1.66; S: 1.82, 1.49–2.23; and C+S: 1.49, 1.38, 1.62). Predictors for high vaccination initiation included vaccine recommendation since 1999 vs 2006 (2.87, 2.63–3.13); exemption of enforcement (most restrictive vs lenient: 2.10, 1.68–2.63). In addition, non-White, Hispanic children aged between 19–35 months with insurance, >$75,000 family income household, mothers having college degree were more likely to initiate Hep A vaccination. The associations were similar for Hep A vaccination completion. Figure 1. Hep A vaccination initiation and completion rates between pre- and post-requirement periods (C=childcare entry requirement only; S=school entry requirement only; and C+S=childcare AND school entry requirement) Table 1. Multivariate association between state policy and vaccination initiation and completion rate Conclusion States with childcare and school entry requirements are more likely to initiate and complete Hep A vaccine compared to those without such policy. This interventional policy may help to control and prevent Hep A outbreaks in states where it is applied. Disclosures Yoonyoung Choi, PhD, MS, RPh, Merck (Employee) Alexandra Bhatti, JD, MPH, Merck (Employee) Zhiwen Liu, PhD, Merck & Co., Inc., (Employee) Michelle Goveia, MD, Merck & Co., Inc (Employee, Shareholder) Jakub Simon, MD, MS, Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee, Shareholder)

Background The recent Ebola virus disease (EVD) outbreak in the Democratic Republic of the Congo highlights the sustained threat of EVD morbidity and mortality where healthcare and vaccine delivery are challenging. ERVEBO®, a live recombinant vesicular stomatitis virus (VSV) vaccine containing the Zaire ebolavirus glycoprotein (GP) in place of the VSV GP (rVSVΔG-ZEBOV-GP), was developed by Merck & Co., Inc., Kenilworth, NJ, USA in collaboration with multiple partners to prevent EVD and has been approved for human use in several countries. Methods We pooled data from three Phase 2/3 clinical trials conducted in Guinea (FLW), Sierra Leone (STRIVE), and Liberia (PREVAIL) during the 2013–2016 West African outbreak to assess immune responses using a validated assay in each of the three studies and performed a post hoc analysis by sex, age (18–50 yrs & >50 yrs) and baseline (BL) GP-enzyme-linked immunosorbent assay (ELISA) titer (< 200 & ≥200 EU/ml). The full analysis set (FAS) population included the primary immunogenicity populations (all vaccinated participants with serology data collected within an acceptable day range) from all three trials. The endpoints were total IgG antibody response (EU/mL) measured by the GP-ELISA and neutralizing antibody response measured by the plaque reduction neutralization test (PRNT) to rVSVΔG-ZEBOV-GP at Days 14, 28, 180, and 365 postvaccination. Results In the overall population and in all subgroups, GP-ELISA and PRNT geometric mean titers increased from BL, with most peaking at Day 28 and persisting through Day 365. There were differences between males and females and between participants with BL GP-ELISA < 200 & ≥200 EU/ml. There did not appear to be a difference between age groups. Conclusion These data demonstrate that rVSVΔG-ZEBOV-GP elicits a robust and durable immune response up to 12 months in participants regardless of age, sex, or BL GP-ELISA titer. The higher immune responses observed in females and participants with preexisting immunity are consistent with those described in published literature for other vaccines. Disclosures Jakub Simon, MD, MS, Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee, Shareholder) Stephen Kennedy, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Scientific Research Study Investigator) Barbara Mahon, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee, Shareholder) Sheri Dubey, MS, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee, Shareholder) Rebecca Grant-Klein, PhD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee, Shareholder) Ken Liu, PhD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee, Shareholder) Jonathan Hartzel, PhD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee, Shareholder) Beth-Ann Coller, PhD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee, Shareholder) Carolee Welebob, PhD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee, Shareholder) Mary Hanson, PhD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee, Shareholder) Rebecca Grais, PhD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Scientific Research Study Investigator)

Aging is accompanied by a decline in immune function which can lead to decreased responses to vaccines. Attenuated recombinant Vibrio cholerae O1 vaccine strain CVD 103-HgR elicits a rapid serum vibriocidal antibody (SVA) response and protects against cholera diarrhea in volunteer challenge studies but has not been studied in older adults. We evaluated CVD 103-HgR (PXVX0200) in adults age 46–64, compared them to previously studied adults age 18–45, and studied age-related immunogenicity across adults 18–64 years of age. Volunteers were randomized to receive a single dose of 1 × 109 CFU of PXVX0200 or placebo. Immunogenicity endpoints included SVA and anti-cholera toxin (CT) antibody levels on days 1, 11, 29, 91 and 181 and lipopolysaccharide (LPS) and CT-specific IgA and IgG memory B cells on days 1, 91 and 181. Safety was assessed by comparing solicited signs and symptoms on days 1–8 and other adverse events through day 181. 2979 volunteers received vaccine, including 291 age 45–64. Day 11 seroconversion occurred in 90.4% of older adults vs 93.5%% of younger adults and met the endpoint of demonstrating non-inferiority between the two groups. Significant increases in LPS-specific IgG and IgA and CT-specific memory IgG memory B cells were seen at days 91 and 181. There appeared to be a continuous age-related decline in SVA seroconversion and geometric mean titers, but not memory B cell responses, across the 18–64 year age range. Most reactogenicity was mild and was more common in the placebo group. PXVX0200 appears safe and immunogenic in older adults. Clinical Trials Registration: clinicaltrials.gov NCT02100631.

We refine and clinically parameterize a mathematical model of the humoral immune response against Shigella, a diarrheal bacteria that infects 80-165 million people and kills an estimated 600,000 people worldwide each year. Using Latin hypercube sampling and Monte Carlo simulations for parameter estimation, we fit our model to human immune data from two Shigella EcSf2a-2 vaccine trials and a rechallenge study in which antibody and B-cell responses against Shigella′s lipopolysaccharide (LPS) and O-membrane proteins (OMP) were recorded. The clinically grounded model is used to mathematically investigate which key immune mechanisms and bacterial targets confer immunity against Shigella and to predict which humoral immune components should be elicited to create a protective vaccine against Shigella. The model offers insight into why the EcSf2a-2 vaccine had low efficacy and demonstrates that at a group level a humoral immune response induced by EcSf2a-2 vaccine or wild-type challenge against Shigella′s LPS or OMP does not appear sufficient for protection. That is, the model predicts an uncontrolled infection of gut epithelial cells that is present across all best-fit model parameterizations when fit to EcSf2a-2 vaccine or wild-type challenge data. Using sensitivity analysis, we explore which model parameter values must be altered to prevent the destructive epithelial invasion by Shigella bacteria and identify four key parameter groups as potential vaccine targets or immune correlates: 1) the rate that Shigella migrates into the lamina propria or epithelium, 2) the rate that memory B cells (BM) differentiate into antibody-secreting cells (ASC), 3) the rate at which antibodies are produced by activated ASC, and 4) the Shigella-specific BM carrying capacity. This paper underscores the need for a multifaceted approach in ongoing efforts to design an effective Shigella vaccine.

[This corrects the article DOI: 10.1371/journal.pone.0189571.].

Reactive immunization with a single-dose cholera vaccine that could rapidly (within days) protect immunologically naive individuals during virgin soil epidemics, when cholera reaches immunologically naive populations that have not experienced cholera for decades, would facilitate cholera control. One dose of attenuated Vibrio cholerae O1 classical Inaba vaccine CVD 103-HgR (Vaxchora) containing ≥2 × 10 8 CFU induces vibriocidal antibody seroconversion (a correlate of protection) in >90% of U.S. adults. A previous CVD 103-HgR commercial formulation required ≥2 × 10 9 CFU to elicit high levels of seroconversion in populations in developing countries. We compared the vibriocidal responses of Malians (individuals 18 to 45 years old) randomized to ingest a single ≥2 × 10 8 -CFU standard dose ( n = 50) or a ≥2 × 10 9 -CFU high dose ( n = 50) of PaxVax CVD 103-HgR with buffer or two doses ( n = 50) of Shanchol inactivated cholera vaccine (the immunologic comparator). To maintain blinding, participants were dosed twice 2 weeks apart; CVD 103-HgR recipients ingested placebo 2 weeks before or after ingesting vaccine. Seroconversion (a ≥4-fold vibriocidal titer rise) between the baseline and 14 days after CVD 103-HgR ingestion and following the first and second doses of Shanchol were the main outcomes measured. By day 14 postvaccination, the rates of seroconversion after ingestion of a single standard dose and a high dose of CVD 103-HgR were 71.7% (33/46 participants) and 83.3% (40/48 participants), respectively. The rate of seroconversion following the first dose of Shanchol, 56.0% (28/50 participants), was significantly lower than that following the high dose of CVD 103-HgR ( P = 0.003). The vibriocidal geometric mean titer (GMT) of the high dose of CVD 103-HgR exceeded the GMT of the standard dose at day 14 (214 versus 95, P = 0.045) and was ∼2-fold higher than the GMT on day 7 and day 14 following the first Shanchol dose ( P > 0.05). High-dose CVD 103-HgR is recommended for accelerated evaluation in developing countries to assess its efficacy and practicality in field situations. (This study has been registered at ClinicalTrials.gov under registration no. NCT02145377.)

The Ebola virus disease outbreak that began in Western Africa in December 2013 was unprecedented in both scope and spread, and the global response was slower and less coherent than was optimal given the scale and pace of the epidemic. Past experience with limited localized outbreaks, lack of licensed medical countermeasures, reluctance by first responders to direct scarce resources to clinical research, community resistance to outside interventions, and lack of local infrastructure were among the factors delaying clinical research during the outbreak. Despite these hurdles, the global health community succeeded in accelerating Ebola virus vaccine development, in a 5-month interval initiating phase I trials in humans in September 2014 and initiating phase II/III trails in February 2015. Each of the three Ebola virus disease-affected countries, Sierra Leone, Guinea, and Liberia, conducted a phase II/III Ebola virus vaccine trial. Only one of these trials evaluating recombinant vesicular stomatitis virus expressing Ebola virus glycoprotein demonstrated vaccine efficacy using an innovative mobile ring vaccination trial design based on a ring vaccination strategy responsible for eradicating smallpox that reached areas of new outbreaks. Thoughtful and intensive community engagement in each country enabled the critical community partnership and acceptance of the phase II/III in each country. Due to the delayed clinical trial initiation, relative to the epidemiologic peak of the outbreak in the three countries, vaccine interventions may or may not have played a major role in bringing the epidemic under control. Having demonstrated that clinical trials can be performed during a large outbreak, the global research community can now build on the experience to implement trials more rapidly and efficiently in future outbreaks. Incorporating clinical research needs into planning for future health emergencies and understanding what kind of trial designs is needed for reliable results in an epidemic of limited duration should improve global response to future infectious disease outbreaks.

Immunologic correlates of protection can be used to infer vaccine efficacy for populations in which challenge trials or field studies are infeasible. In a recent cholera challenge trial (W. H. Chen et al., Clin Infect Dis 62:1329–1335, 2016, https://doi.org/10.1093/cid/ciw145 ), 134 North American cholera-naive volunteers were randomized to receive either the live, attenuated single-dose cholera vaccine CVD (Center for Vaccine Development) 103-HgR or placebo, and the titers of vibriocidal antibodies against the classical Inaba strain were assessed at 10 days after treatment. Subsequent to the immunologic evaluation, each subject ingested a fixed quantity of virulent Vibrio cholerae O1 El Tor Inaba. Data from this trial suggest that the vaccine-induced increase in the vibriocidal antibody titer prior to challenge is tightly linked with protection: 51/51 vaccinees with postvaccination vibriocidal antibody titers of ≥2,560 were protected against moderate/severe diarrhea, and 60/62 vaccinees who seroconverted or experienced a 4-fold or greater increase in vibriocidal antibody titer relative to prevaccination levels were similarly protected. Atypically high vibriocidal antibody titers were observed in some placebo subjects; protection was limited in these individuals and differed substantially from the level of protection experienced by vaccinees with the same postvaccination titers. Since only 1 of 66 placebo recipients experienced seroconversion, seroconversion was found to be uniquely associated with vaccination and insensitive to the effects of factors that can cause titers to be elevated but are weakly associated with protection. Thus, vibriocidal antibody seroconversion was found to be better than the vibriocidal antibody titer for inferring vaccine efficacy in cholera-naive populations for which studies based upon exposure to V. cholerae are impractical. (This study has been registered at ClinicalTrials.gov under registration no. NCT01895855.)

Background Immunologic correlates of protection are important in vaccine development because they give insight into mechanisms of protection, assist in the identification of promising vaccine candidates, and serve as endpoints in bridging clinical vaccine studies. Our goal is the development of a methodology to identify immunologic correlates of protection using the Shigella challenge as a model. Methods The proposed methodology utilizes the Random Forests (RF) machine learning algorithm as well as Classification and Regression Trees (CART) to detect immune markers that predict protection, identify interactions between variables, and define optimal cutoffs. Logistic regression modeling is applied to estimate the probability of protection and the confidence interval (CI) for such a probability is computed by bootstrapping the logistic regression models. Results The results demonstrate that the combination of Classification and Regression Trees and Random Forests complements the standard logistic regression and uncovers subtle immune interactions. Specific levels of immunoglobulin IgG antibody in blood on the day of challenge predicted protection in 75 % ( 95 % CI 67–86). Of those subjects that did not have blood IgG at or above a defined threshold, 100 % were protected if they had IgA antibody secreting cells above a defined threshold. Comparison with the results obtained by applying only logistic regression modeling with standard Akaike Information Criterion for model selection shows the usefulness of the proposed method. Conclusion Given the complexity of the immune system, the use of machine learning methods may enhance traditional statistical approaches. When applied together, they offer a novel way to quantify important immune correlates of protection that may help the development of vaccines.

Background Antibodies targeting O-specific polysaccharide (OSP) of Vibrio cholerae may protect against cholera; however, little is known about this immune response in infected immunologically naïve humans. Methodology We measured serum anti-OSP antibodies in adult North American volunteers experimentally infected with V. cholerae O1 Inaba El Tor N16961. We also measured vibriocidal and anti-cholera toxin B subunit (CtxB) antibodies and compared responses to those in matched cholera patients in Dhaka, Bangladesh, an area endemic for cholera. Principal findings We found prominent anti-OSP antibody responses following initial cholera infection: these responses were largely IgM and IgA, and highest to infecting serotype with significant cross-serotype reactivity. The anti-OSP responses peaked 10 days after infection and remained elevated over baseline for ≥ 6 months, correlated with vibriocidal responses, and may have been blunted in blood group O individuals (IgA anti-OSP). We found significant differences in immune responses between naïve and endemic zone cohorts, presumably reflecting previous exposure in the latter. Conclusions Our results define immune responses to O-specific polysaccharide in immunologically naive humans with cholera, find that they are largely IgM and IgA, may be blunted in blood group O individuals, and differ in a number of significant ways from responses in previously humans. These differences may explain in part varying degrees of protective efficacy afforded by cholera vaccination between these two populations. Trial registration number ClinicalTrials.gov NCT01895855., Author summary Cholera is an acute, secretory diarrheal disease caused by Vibrio cholerae O1. There is a growing body of evidence that immune responses targetting the O-specific polysaccharide (OSP) of V. cholerae are associated with protecton against cholera. Despite this, little is known about immune responses targeting OSP in immunologically naive individals. Cholera affects populations in severely resource-limited areas. To address this, we assessed anti-OSP immune responses in North American volunteers experimentally infected with wild type V. cholerae O1 El Tor Inaba strain N16961. We found that antibody responses were largely IgM and IgA, cross-reacted to both Inaba and Ogawa serotypes, and correlated with vibriocidal responses. We found no association of responses to severity of disease, but did find that blood group O individuals mounted lower IgA fold-changes to OSP than did non-blood group O individuals. Individuals with blood group O are at particular risk for severe cholera, and are less well protected against cholera following oral vaccination. We also compared anti-OSP responses in previously unexposed individuals to responses in matched endemic zone patients, and found a number of significant differences. Such differences may explain in part the varying degrees of protective efficacy afforded by cholera vaccination between these two populations.

One potential advantage of live attenuated bacterial vaccines is the ability to stimulate responses to antigens which are only expressed during the course of infection. To determine whether the live attenuated cholera vaccine CVD 103-HgR (Vaxchora) results in antibody responses to the in vivo -induced toxin-coregulated pilus antigen TcpA, we measured IgA and IgG responses to Vibrio cholerae O1 El Tor TcpA in a subset of participants in a recently reported experimental challenge study. Participants were challenged with V. cholerae O1 El Tor Inaba N16961 either 10 days or 90 days after receiving the vaccine or a placebo. Neither vaccination nor experimental infection with V. cholerae alone resulted in a robust TcpA IgG or IgA response, but each did elicit a strong response to cholera toxin. However, compared to placebo recipients, vaccinees had a marked increase in IgG TcpA antibodies following the 90-day challenge, suggesting that vaccination with CVD 103-HgR resulted in priming for a subsequent response to TcpA. No such difference between vaccine and placebo recipients was observed for volunteers challenged 10 days after vaccination, indicating that this was insufficient time for vaccine-induced priming of the TcpA response. The priming of the response to TcpA and potentially other antigens expressed in vivo by attenuated V. cholerae may have relevance to the maintenance of immunity in areas where cholera is endemic.

The Ebola virus disease outbreak that began in Western Africa in December 2013 was unprecedented in both scope and spread, and the global response was slower and less coherent than was optimal given the scale and pace of the epidemic. Past experience with limited localized outbreaks, lack of licensed medical countermeasures, reluctance by first responders to direct scarce resources to clinical research, community resistance to outside interventions, and lack of local infrastructure were among the factors delaying clinical research during the outbreak. Despite these hurdles, the global health community succeeded in accelerating Ebola virus vaccine development, in a 5-month interval initiating phase I trials in humans in September 2014 and initiating phase II/III trails in February 2015. Each of the three Ebola virus disease-affected countries, Sierra Leone, Guinea, and Liberia, conducted a phase II/III Ebola virus vaccine trial. Only one of these trials evaluating recombinant vesicular stomatitis virus expressing Ebola virus glycoprotein demonstrated vaccine efficacy using an innovative mobile ring vaccination trial design based on a ring vaccination strategy responsible for eradicating smallpox that reached areas of new outbreaks. Thoughtful and intensive community engagement in each country enabled the critical community partnership and acceptance of the phase II/III in each country. Due to the delayed clinical trial initiation, relative to the epidemiologic peak of the outbreak in the three countries, vaccine interventions may or may not have played a major role in bringing the epidemic under control. Having demonstrated that clinical trials can be performed during a large outbreak, the global research community can now build on the experience to implement trials more rapidly and efficiently in future outbreaks. Incorporating clinical research needs into planning for future health emergencies and understanding what kind of trial designs is needed for reliable results in an epidemic of limited duration should improve global response to future infectious disease outbreaks.

Background This study (NCT02503202) evaluated the safety of recombinant vesicular stomatitis virus-Zaire Ebola virus envelope glycoprotein vaccine (rVSVΔG-ZEBOV-GP). Methods Overall, 1197 subjects were randomized 2:2:2:2:1; 1194 were vaccinated with 1 dose of 1 of 3 lots of rVSVΔG- ZEBOV-GP (2 × 107 plaque-forming units [pfu], n = 797; combined-lots group), a single high-dose lot of rVSVΔG-ZEBOV-GP (1 × 108 pfu, n = 264; high-dose group), or placebo (n = 133). Daily temperatures and adverse events (AEs) were recorded days 1 to 42 postvaccination. Solicited AEs included injection-site AEs from days 1 to 5, and joint pain, joint swelling, vesicular lesions (blisters), and rashes from days 1 to 42. Serious AEs (SAEs) were recorded through 6 months postvaccination. Results Fever (≥38.0°C) was observed in 20.2% of combined lots (3.2% with ≥39.0°C), 32.2% of high-dose (4.3% with ≥39.0°C), and 0.8% of placebo (0.8% with ≥39.0°C). Incidences of AEs of interest (days 1-42) were arthralgia (17.1% combined lots, 20.4% high-dose, 3.0% placebo), arthritis (5.1% combined lots, 4.2% high-dose, 0.0% placebo), and rash (3.8% combined lots, 3.8% high-dose, 1.5% placebo). Twenty-one SAEs and 2 deaths were reported, all assessed by investigators as unrelated to vaccine. Conclusions rVSVΔG-ZEBOV-GP was generally well-tolerated, with increased rates of injection-site and systemic AEs compared to placebo, and no vaccine-related SAEs or deaths. These findings support the use of rVSVΔG-ZEBOV-GP vaccine in persons at risk for Ebola virus disease. Clinical trials registration NCT02503202.

Background. Enteroaggregative Escherichia coli (EAEC) is a cause of epidemic and sporadic diarrhea, yet its role as an enteric pathogen is not fully understood. Methods. We characterized 121 EAEC strains isolated in 2008 as part of a case-control study of moderate to severe acute diarrhea among children 0–59 months of age in Bamako, Mali. We applied multiplex polymerase chain reaction and comparative genome hybridization to identify potential virulence factors among the EAEC strains, coupled with classification and regression tree modeling to reveal combinations of factors most strongly associated with illness. Results. The gene encoding the autotransporter protease SepA, originally described in Shigella species, was most strongly associated with diarrhea among the EAEC strains tested (odds ratio, 5.6 [95% confidence interval, 1.92–16.17]; P = .0006). In addition, we identified 3 gene combinations correlated with diarrhea: (1) a clonal group positive for sepA and a putative hemolysin; (2) a group harboring the EAST-1 enterotoxin and the flagellar type H33 but no other previously identified EAEC virulence factor; and (3) a group carrying several of the typical EAEC virulence genes. Conclusion. Our data suggest that only a subset of EAEC strains are pathogenic in Mali and suggest that sepA may serve as a valuable marker for the most virulent isolates.

Background Jet injectors (JIs) avoid safety drawbacks of needle–syringe (N–S) while generating similar immune responses. A new generation of disposable-syringe jet injectors (DSJIs) overcomes the cross-contamination risk of multi-use-nozzle devices used in 20th-century campaigns. In the first study in humans, the newly-US-licensed LectraJet® model M3 RA DSJI was compared to N–S. Methods Sixty healthy adults received one 0.5 mL intramuscular dose of the 2009–2010 seasonal, trivalent, inactivated influenza vaccine (TIV) in randomized, double-masked fashion by either DSJI (n = 30) or N–S (n = 30). Adverse reactions were monitored for 90 days after injection, and serologic responses assayed by hemagglutination inhibition (HI) at days 28 and 90. Results There were no related serious adverse events (SAEs), nor differing rates of unsolicited AEs between DSJI and N–S. Solicited erythema and induration occurred more often after DSJI, but were transient and well-tolerated; a trend was noted for fewer systemic reactions by DSJI. Pre-vaccination HI geometric mean titers (GMT) increased by 28 days for H1N1, H3N2, and B antigens by 13-, 14-, and 8-fold via DSJI, and by 7-, 10-, and 7-fold for N–S, respectively. No trending differences in GMT, seroconversion, or seroprotection were noted; sample sizes precluded non-inferiority assessment. Conclusions DSJI delivery of TIV is well-tolerated and immunogenic.

We studied the induction of antigen-specific IgA memory B cells (B(M)) in volunteers who received live attenuated Shigella flexneri 2a vaccines. Subjects ingested a single oral dose of 10(7), 10(8) or 10(9) CFU of S. flexneri 2a with deletions in guaBA (CVD 1204) or in guaBA, set and sen (CVD 1208). Antigen-specific serum and stool antibody responses to LPS and Ipa B were measured on days 0, 7, 14, 28 and 42. IgA B(M) cells specific to LPS, Ipa B and total IgA were assessed on days 0 and 28. We show the induction of significant LPS-specific IgA B(M) cells in anti-LPS IgA seroresponders. Positive correlations were found between anti-LPS IgA B(M) cells and anti-LPS IgA in serum and stool; IgA B(M) cell responses to IpaB were also observed. These B(M) cell responses are likely play an important role in modulating the magnitude and longevity of the humoral response.

Measles remains an important cause of morbidity and mortality among children in the developing world. The goal of this study was to examine measles virus-specific mucosal immune responses in healthy immune ( n = 24; plaque reduction neutralization [PRN] titers of ≥200 mIU/ml) and nonimmune ( n = 24) young adult volunteers who received the monovalent Moraten measles vaccine via intranasal (spray delivery) or subcutaneous immunization. Serum, oral fluid, and nasal wash samples were examined for measles virus-specific and total IgG and IgA on day 0 (prior to vaccination) and on days 14, 28, and 90 after vaccination. Nonimmune subjects vaccinated subcutaneously developed high levels of measles virus PRN, IgG, and IgA antibodies in serum, oral fluid, and nasal washes. Total IgG and secretory IgA (sIgA) titers were increased in nasal washes, and total IgG was increased in oral fluid specimens. There was a strong correlation between PRN and measles virus-specific IgG titers measured in serum, oral fluid, and nasal washes, whereas a weak correlation was found between PRN and measles virus-specific IgA titers. Notably, intranasal measles vaccination resulted in increased production of measles virus-specific sIgA in oral fluid and nasal washes in nonimmune individuals, without evidence of a systemic immune response. In contrast, no significant vaccine-induced responses were observed in immune subjects, regardless of the route of immunization. These results demonstrate that (i) intranasal measles immunization can elicit a mucosal response independent of the induction of serum antibodies and (ii) both mucosal and systemic antibody responses following nasal or subcutaneous immunization are blunted by preexisting measles immunity.

Understanding the mechanisms underlying the induction of immunity in the gastrointestinal mucosa following oral immunization and the cross-talk between mucosal and systemic immunity should expedite the development of vaccines to diminish the global burden caused by enteric pathogens. Identifying an immunological correlate of protection in the course of field trials of efficacy, animal models (when available), or human challenge studies is also invaluable. In industrialized country populations, live attenuated vaccines (e.g. polio, typhoid, and rotavirus) mimic natural infection and generate robust protective immune responses. In contrast, a major challenge is to understand and overcome the barriers responsible for the diminished immunogenicity and efficacy of the same enteric vaccines in underprivileged populations in developing countries. Success in developing vaccines against some enteric pathogens has heretofore been elusive (e.g. Shigella). Different types of oral vaccines can selectively or inclusively elicit mucosal secretory immunoglobulin A and serum immunoglobulin G antibodies and a variety of cell-mediated immune responses. Areas of research that require acceleration include interaction between the gut innate immune system and the stimulation of adaptive immunity, development of safe yet effective mucosal adjuvants, better understanding of homing to the mucosa of immunologically relevant cells, and elicitation of mucosal immunologic memory. This review dissects the immune responses elicited in humans by enteric vaccines.

Background Cholera is an acute voluminous dehydrating diarrheal disease caused by toxigenic strains of Vibrio cholerae O1 and occasionally O139. A growing body of evidence indicates that immune responses targeting the O-specific polysaccharide (OSP) of V. cholerae are involved in mediating protection against cholera. We therefore assessed whether antibody responses against OSP occur after vaccination with live attenuated oral cholera vaccine CVD 103-HgR, and whether such responses correlate with protection against cholera. Methodology We assessed adult North American volunteers (n = 46) who were vaccinated with 5 × 108 colony-forming units (CFU) of oral cholera vaccine CVD 103-HgR and then orally challenged with approximately 1 × 105 CFU of wild-type V. cholerae O1 El Tor Inaba strain N16961, either 10 or 90 days post-vaccination. Principal findings Vaccination was associated with induction of significant serum IgM and IgA anti-OSP and vibriocidal antibody responses within 10 days of vaccination. There was significant correlation between anti-OSP and vibriocidal antibody responses. IgM and IgA anti-OSP responses on day 10 following vaccination were associated with lower post-challenge stool volume (r = −0.44, P = 0.002; r = −0.36, P = 0.01; respectively), and none of 27 vaccinees who developed a ≥1.5 fold increase in any antibody isotype targeting OSP on day 10 following vaccination compared to baseline developed moderate or severe cholera following experimental challenge, while 5 of 19 who did not develop such anti-OSP responses did (P = 0.01). Conclusion Oral vaccination with live attenuated cholera vaccine CVD 103-HgR induces antibodies that target V. cholerae OSP, and these anti-OSP responses correlate with protection against diarrhea following experimental challenge with V. cholerae O1. Trial registration ClinicalTrials.gov NCT01895855, Author summary Cholera is a severe watery diarrheal disease, caused by pathogenic strains of V. cholerae. Protective immunity against cholera is serogroup specific, and serogroup specificity is determined by the O-specific polysaccharide (OSP) of V. cholerae lipopolysaccharide (LPS). Despite this, no previous work has directly assessed correlation of OSP-immune responses and protection against cholera. In this study, we assessed adult North American volunteer’s antibody responses targeting OSP after vaccination with live attenuated oral cholera vaccine CVD 103-HgR, and we assessed correlation of protection against cholera with such antibody responses. Oral vaccination was associated with the induction of significant IgM and IgA responses against OSP, and these responses correlated with vibriocidal responses. There was significant negative correlation of OSP responses and post-challenge stool volume, and none of the volunteers who developed an anti-OSP antibody responses of any isotype of ≥1.5 fold developed moderate or severe cholera following experimental challenge. In summary, vaccination with live attenuated oral cholera vaccine CVD 103-HgR induces antibodies that target V. cholerae OSP, and these responses highly correlate with protection against cholera.

Purpose of review To summarize recent advances that contribute to the development of new vaccines against gastrointestinal infections. Recent findings The main themes of this review include epidemiology assessing disease burden of enteric pathogens, increasing antibiotic resistance, positive effect of existing enteric vaccines in developed and developing countries, and recommendations of advisory bodies; antigen discovery and preclinical testing, including live vector systems expressing heterologous antigens, conjugation of antigen to carrier proteins, and plant-based expression systems; as well as clinical studies highlighting recently published enteric vaccine candidates, studies assessing immune correlates of protection, as well as a trend for technology transfer to developing countries where enteric vaccines can be produced less expensively. Summary It is an exciting time for the development of novel vaccines against gastrointestinal infections. Better understanding of disease burden, interest from funding sources, identification of novel antigens, better understanding of protective immune responses, and steady progress in the conduct of clinical trials make the development of new enteric vaccines a goal that is attainable in the near future.

We evaluated B memory responses in healthy adult volunteers who received one oral dose of live-attenuated Shigella flexneri 2a vaccine. LPS-specific B(M) cells increased from a median of 0 at baseline to 20 spot forming cells (SFC)/10(6) expanded cells following vaccination (p=0.008). A strong correlation was found between post-vaccination anti-LPS B(M) cell counts and peak serum anti-LPS IgG titers (rs=0.95, p=0.0003). Increases in B(M) specific for IpaB approaching significance were also observed. In sum, oral vaccination with live-attenuated S. flexneri 2a elicits B(M) cells to LPS and IpaB, suggesting that B(M) responses to Shigella antigens should be further studied as a suitable surrogate of protection in shigellosis.

Currently, there is no licensed Shigella vaccine; however, various promising live-attenuated vaccine candidates have emerged, including CVD1208S (ΔguaBA, Δset, Δsen S. flexneri 2a), which was shown to be safe and immunogenic in Phase 1 clinical trials. Here, we report the immune responses elicited in an outpatient Phase 2 clinical trial in which subjects were vaccinated with CVD 1208S. Oral immunization with CVD 1208S elicited high anti-S. flexneri 2a LPS and IpaB antibody responses as well as an acute plasmablast (PB) infiltration in peripheral blood 7 days after immunization. PB sorted based on their expression of homing molecules confirmed that cells expressing integrin α4β7 alone or in combination with CD62L were responsible for antibody production (as measured by ELISpot). Furthermore, using high-color flow-cytometry, on day 7 after immunization, we observed the appearance of conventional PB (CPB, CD19(dim) CD20(-) CD27(+high) CD38(+high) CD3(-)), as well as a PB population that did not express CD27 (CD27(-) PB; pre-plasmablasts). The pattern of individual or simultaneous expression of homing markers (integrin α4β7, CD62L, CXCR3, and CXCR4) suggested that CPB cells homed preferentially to the inflamed gut mucosa. In contrast, ~50% CD27(-) PB cells appear to home to yet to be identified peripheral lymphoid organs or were in a transition state preceding integrin α4β7 upregulation. In sum, these observations demonstrate that strong immune responses, including distinct PB subsets with the potential to home to the gut and other secondary lymphoid organs, can be elicited after a short time of exposure to a shigella oral vaccine.

We establish a mathematical framework for studying immune interactions with Shigella, a bacteria that kills over one million people worldwide every year. The long-term goal of this novel approach is to inform Shigella vaccine design by elucidating which immune components and bacterial targets are crucial for establishing Shigella immunity. Our delay differential equation model focuses on antibody and B cell responses directed against antigens like lipopolysaccharide in Shigella’s outer membrane. We find that antibody-based vaccines targeting only surface antigens cannot elicit sufficient immunity for protection. Additional boosting prior to infection would require a four-orders-of-magnitude increase in antibodies to sufficiently prevent epithelial invasion. However, boosting anti-LPS B memory can confer protection, which suggests these cells may correlate with immunity. We see that IgA antibodies are slightly more effective per molecule than IgG, but more total IgA is required due to spatial functionality. An extension of the model reveals that targeting both LPS and epithelial entry proteins is a promising avenue to advance vaccine development. This paper underscores the importance of multifaceted immune targeting in creating an effective Shigella vaccine. It introduces mathematical models to the Shigella vaccine development effort and lays a foundation for joint theoretical/experimental/clinical approaches to Shigella vaccine design.

The role of Shigella-specific B memory (BM) in protection has not been evaluated in human challenge studies. We utilized cryopreserved pre- and post-challenge peripheral blood mononuclear cells and sera from wild-type Shigella flexneri 2a (wt-2457T) challenges. Challenged volunteers were either naive or subjects who had previously ingested wt-2457T or been immunized with hybrid Escherichia coli-Shigella live oral candidate vaccine (EcSf2a-2). BM and antibody titers were measured against lipopolysaccharide (LPS) and recombinant invasion plasmid antigen B (IpaB); results were correlated with disease severity following challenge. Pre-challenge IgA IpaB-BM and post-challenge IgA LPS-BM in the previously exposed subjects negatively correlated with disease severity upon challenge. Similar results were observed with pre-challenge IgG anti-LPS and anti-IpaB titers in vaccinated volunteers. Inverse correlations between magnitude of pre-challenge IgG antibodies to LPS and IpaB, as well as IgA IpaB-BM and post-challenge IgA LPS-BM with disease severity suggest a role for antigen-specific BM in protection.

Attenuated live oral typhoid vaccine candidate CVD 909 constitutively expresses Salmonella Typhi capsular polysaccharide antigen (Vi). A randomized, double-blind, heterologous prime–boost clinical study was conducted to determine whether immunity to licensed parenteral Vi vaccine could be enhanced by priming with CVD 909. Priming with CVD 909 elicited higher and persistent, albeit not significant, anti-Vi IgG and IgA following immunization with Vi, than placebo-primed recipients. Vi-specific IgA B memory (B M ) cells were significantly increased in CVD 909-primed subjects. S. Typhi-specific LPS and flagella IgA B M cells were observed in subjects immunized with CVD 909 or with the licensed Vi-negative oral typhoid vaccine Ty21a. CVD 909-induced B M cells exhibited a classical B M phenotype (i.e., CD3 − CD19 + IgD − CD27 + ). This is the first demonstration of classical B M cells specific for bacterial polysaccharide or protein antigens following typhoid immunization. The persistent IgA B M responses demonstrate the capacity of oral typhoid vaccines to prime mucosally relevant immune memory.

A previous Phase 1 trial demonstrated that Shigella flexneri 2a deleted in guaBA, sen and set (strain CVD 1208) is well-tolerated and immunogenic after a single oral dose of 10(8) or 10(9) CFU. To facilitate further clinical development, the strain was reconstructed using animal-free media to conform to regulatory guidelines, and designated CVD1208S. Healthy inpatient volunteers were randomized (double-blind) to receive a single oral dose of either CVD 1208S (10(8) [n = 7] or 10(9) [n = 7] CFU) or placebo (n = 2). Both vaccine dosage levels were generally well-tolerated. Anti-lipopolysaccharide responses, measured as IgA antibody secreting cells, serum IgG, or fecal IgA levels, occurred in 7 (100%), three (43%) and two (29%) subjects following inoculation with 10(9) CFU, respectively. Interferon gamma production in response to Shigella antigens was observed in 1 of 4 (25%) and 4 of 7 (57%) subjects, following inoculation with 10(8) and 10(9) CFU. We conclude that CVD 1208S retains a favorable safety and immunogenicity profile after reconstruction on animal-free media, comparable to that seen with CVD 1208, which was constructed on media containing animal products, and shows promise as a live, oral Shigella vaccine.

Despite the availability of a safe and effective vaccine for over four decades, measles remains one of the most common infectious disease killers of children in the world. Mucosal administration of currently licensed measles vaccine has been proposed to address issues of needle safety and improve vaccine uptake.Healthy adult volunteers were randomized to receive live-attenuated monovalent measles virus vaccine (Moraten Berna) via the standard subcutaneous (SQ) or the experimental intranasal (IN) route in a randomized, double-masked fashion. Safety, reactogenicity, immunogenicity, and shedding were assessed.Safety, reactogenicity, and viral shedding were not significantly different in the two study groups. Immunogenicity was markedly lower in the group of volunteers that received vaccine via the IN route. Plaque reduction neutralization (PRN) geometric mean titers (GMT) were 125 (95% confidence interval [CI] 68-228) milli International Units per milliliter (mIU/mL) on day 28 in recipients of IN vaccine versus 645 (95% CI 468-889) mIU/mL in recipients of vaccine SQ; p0.001 by Mann-Whitney Rank Sum. 50% of measles non-immune individuals mounted titers above the protective threshold of PRN 200 mIU/mL after IN administration versus 100% of volunteers who received the vaccine SQ.Intranasal administration of live-attenuated measles vaccine was safe and well tolerated, but failed to mount significant immune responses when compared to subcutaneous administration. It is possible that higher doses or smaller particle size are necessary for successful intranasal measles vaccination and boosting.

Publisher Summary This chapter reviews the clinical evaluation of adjuvants in vaccine development. It reviews definitions, qualities of an ideal adjuvant, and components of adjuvant development, and discusses regulatory issues as well as examples of licensed and experimental adjuvants in human vaccines. Adjuvants typically have complex and multifactorial immunological mechanisms of action in vivo. Adjuvant safety, including the real and theoretical risks of administering vaccine adjuvants to humans, is a critical component that can enhance or retard the development process. In addition to the problem of safety, other preclinical issues critical to orderly clinical development of adjuvanted vaccines are—variable adjuvanticity, suboptimal use of aluminum adjuvants, inadequate animal models, and the inability to predict consistently protective or therapeutic efficacy by immunoassays. Experimental adjuvants in clinical trials include safer exotoxins, oligonucleotides, derivatives of lipid A other than monophosphoryl lipid (MPL), cytokines, dendritic cells, saponins, montanides, nonionic block copolymers, polyactide (PLG), and combination adjuvants such as AS04.

A case report of an intramedullary spinal cord abscess in a 13-month-old boy and a review of relevant existing pediatric literature is presented. Thirty-eight cases of pediatric intramedullary spinal cord abscess are analyzed for presenting signs and symptoms, microbiology of isolated organisms, surgical intervention, antibiotic administration and outcome. The most significant variable on outcome is timely surgical intervention, followed by appropriate antibiotic administration.