Meeting report: CEPI consultation on accelerating access to novel vaccines against emerging infectious diseases for pregnant and lactating women, London, 12-13 February 2020.

Infectious diseases may cause serious morbidity and mortality in pregnant women, their foetuses, and infants; the risk associated with any newly emerging infectious disease (EID) is likely unknown at the time of its emergence. While the ongoing SARS-CoV-2 pandemic shows that the development of vaccines against new pathogens can be considerably accelerated, the immunization of pregnant women generally lags behind the general population. Guided by the priority pathogen list for WHO's R&D Blueprint for Action to Prevent Epidemics, this workshop sought to define the evidence needed for use of vaccines against EIDs in pregnant and lactating women, using Lassa fever as a model. Close to 60 maternal immunization (MI) and vaccine safety experts, regulators, vaccine developers, Lassa fever experts, and investigators from Lassa-affected countries examined the critical steps for vaccine development and immunization decisions for pregnant and lactating women. This paper reports on key themes and recommendations from the workshop. Current practice still assumes the exclusion of pregnant women from early vaccine trials. A shift in paradigm is needed to progress towards initial inclusion of pregnant women in Phase 2 and 3 trials. Several practical avenues were delineated. Participants agreed that vaccine platforms should be assessed early for their suitability for maternal immunization. It was noted that, in some cases, nonclinical data derived from assessing a given platform using other antigens may be adequate evidence to proceed to a first clinical evaluation and that concurrence from regulators may be sought with supporting rationale. For clinical trials, essential prerequisites such as documenting the disease burden in pregnant women, study site infrastructure, capabilities, and staff experience were noted. Early and sustained communication with the local community was considered paramount in any program for the conduct of MI trials and planned vaccine introduction.

SARS-CoV-2 Variants and Vaccines.

Viral variants of concern may emerge with dangerous resistance to the immunity generated by the current vaccines to prevent coronavirus disease 2019 (Covid-19). Moreover, if some variants of concern have increased transmissibility or virulence, the importance of efficient public health measures and vaccination programs will increase. The global response must be both timely and science based.

Polymicrobial enteric infections in African infants with diarrhoea-results from a longitudinal prospective case-control study.

OBJECTIVES: This longitudinal case-control study aimed to determine the frequency of polymicrobial enteric detections in Ghanaian infants with and without diarrhoea. METHODS: Infants aged 1-12 months with and without diarrhoea attending the outpatient department of a peri-urban Ghanaian hospital were prospectively assessed and stool samples were collected on days 0, 6 and 28 and analysed for 18 enteric pathogens with PCR. RESULTS: At least one enteric pathogen was detected in 100 of 107 cases with diarrhoea (93%) and in 82 of 97 controls (85%). The number of pathogens was higher in cases than in controls (median three versus two pathogens, p 0.001). The adjusted attributable fraction (AF) for diarrhoea was highest for enterotoxigenic Escherichia coli (7.2%, 95% CI -2.0% to 16.3%), rotavirus (4.1%, 95% CI 0.6%-7.5%), Giardia lamblia (2.3%, 95% CI -0.7 to 5.3%) and astrovirus (2.3%, 95% CI -2.9 to 7.5%). In cases, a higher pathogen number was significantly associated with watery stool consistency (median 3, interquartile range (IQR) 2-5 versus median 2.5, IQR 1-4, p 0.014), stool frequency five or more per day (median 4, IQR 3-5 versus median 3, IQR 2-4, p 0.048) and vomiting (median 4, IQR 3-5 versus median 3, IQR 2-4, p 0.025). During follow-up, 94% (78/83) of cases and 85% (67/79) of controls had acquired at least one new pathogen without developing a new episode of diarrhoea. CONCLUSION: Enteric pathogens could be identified in the stool of the vast majority of Ghanaian infants, whereby pathogens were very frequently acquired without resulting in new episodes of diarrhoea during follow-up. A higher number of co-occurring pathogens may increase the risk of diarrhoea and disease severity.

Vaccine-associated enhanced disease: Case definition and guidelines for data collection, analysis, and presentation of immunization safety data.

This is a Brighton Collaboration Case Definition of the term "Vaccine Associated Enhanced Disease" to be utilized in the evaluation of adverse events following immunization. The Case Definition was developed by a group of experts convened by the Coalition for Epidemic Preparedness Innovations (CEPI) in the context of active development of vaccines for SARS-CoV-2 vaccines and other emerging pathogens. The case definition format of the Brighton Collaboration was followed to develop a consensus definition and defined levels of certainty, after an exhaustive review of the literature and expert consultation. The document underwent peer review by the Brighton Collaboration Network and by selected Expert Reviewers prior to submission.

A phase 2 study of the bivalent VLP norovirus vaccine candidate in older adults; impact of MPL adjuvant or a second dose.

INTRODUCTION: Acute norovirus gastroenteritis causes significant morbidity and in uncommon cases fatality in older adults. We investigated the safety and immunogenicity of bivalent virus-like particle (VLP) vaccine candidate formulations with and without monophosphoryl lipid A (adjuvant MPL) in this population. METHODS: In this phase II, double-blind, controlled trial 294 healthy adults, ≥ 60 years of age, were randomized (1:1:1:1) to four groups to receive one or two intramuscular immunizations 28 days apart, with 26 18-49 year-old controls who received one MPL-free dose. One-dose groups received placebo on Day 1. Vaccine formulations contained 15 µg GI.1 and 50 µg GII.4c VLP antigens and 500 µg Al(OH)3, with or without 15 µg MPL. We measured histo-blood group antigen blocking (HBGA) antibodies and ELISA Ig at Days 1, 8, 29, 57, 211 and 393, and avidity indices and cell-mediated immunity (CMI). Solicited local and systemic adverse events (AE) were assessed for 7 days and unsolicited AEs for 28 days after each injection. RESULTS: After one dose HBGA antibodies to both VLP antigens increased with similar kinetics and magnitude in all groups; geometric mean titres (GMTs) persisted above baseline through Day 393. GMTs were similar across age strata (18-49, 60-74, 75-84 and ≥ 85 years of age) and unaffected by a second vaccination or MPL. Total Ig showed similar responses. No clinically relevant differences or changes in avidity or CMI were observed between formulations. Both formulations were well tolerated with no vaccine-related SAEs, the most frequent AEs being mild injection site pain and fatigue. CONCLUSIONS: Adults over 60 years of age displayed no safety concerns and had similar immune responses to the norovirus VLP vaccine candidate as younger adults, unaffected by increasing age, a second dose or inclusion of MPL. This data supports the further development of the MPL-free vaccine candidate for older adults.

Safety and immunogenicity of experimental stand-alone trivalent, inactivated Sabin-strain polio vaccine formulations in healthy infants: A randomized, observer-blind, controlled phase 1/2 trial.

BACKGROUND: To increase the global supply of affordable IPV vaccine, preferably using Sabin viruses to comply with GAPIII requirements, Takeda has assessed three dosages of a stand-alone sIPV. METHODS: In this phase I/II study two cohorts of 40 adults and 60 toddlers, respectively, were initially assessed for safety after receiving high-dosage sIPV compared with placebo (adults) or Salk IPV (toddlers). A cohort of 240 infants was then enrolled and randomized (1:1:1:1) to receive low-, medium- or high-dosage sIPV, or a reference Salk IPV in a three-dose primary schedule at 6, 10 and 14 weeks of age. Parents completed safety diaries for 4 weeks after each dose, and immunogenicity was measured as neutralization antibody titers at baseline and four weeks after vaccination. RESULTS: All vaccinations were generally well-tolerated and sIPV had a comparable safety profile to the control arm in adults or the reference Salk IPV vaccine in toddlers and infants. Infants displayed dosage-dependent immune responses to sIPV when assayed using Sabin strains, which were equivalent to the reference IPV in the high-dosage sIPV group for serotypes 1 and 2, but not for Sabin and Salk serotype 3. Seroconversion rates (SCR) of the low- and medium-dosage groups were significantly lower than the Salk IPV group for both Sabin and Salk serotypes 1 and type 2 (p < 0.05), with no significant differences for Salk or Sabin serotypes 3. Responses to sIPV, particularly to Sabin types 1 and 2, were higher in initially seronegative infants, indicating possible interference by maternally-derived antibodies. CONCLUSIONS: A novel stand-alone Sabin-based IPV vaccine was well tolerated with an acceptable safety profile, but less immunogenic than reference Salk IPV at 6, 10 and 14 weeks of age for Salk serotypes 1 and 2, with apparent interference by maternal antibodies. Additional preclinical assessments will be made before any further clinical development.

Consensus summary report for CEPI/BC March 12-13, 2020 meeting: Assessment of risk of disease enhancement with COVID-19 vaccines.

A novel coronavirus (CoV), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 in Wuhan, China and has since spread as a global pandemic. Safe and effective vaccines are thus urgently needed to reduce the significant morbidity and mortality of Coronavirus Disease 2019 (COVID-19) disease and ease the major economic impact. There has been an unprecedented rapid response by vaccine developers with now over one hundred vaccine candidates in development and at least six having reached clinical trials. However, a major challenge during rapid development is to avoid safety issues both by thoughtful vaccine design and by thorough evaluation in a timely manner. A syndrome of "disease enhancement" has been reported in the past for a few viral vaccines where those immunized suffered increased severity or death when they later encountered the virus or were found to have an increased frequency of infection. Animal models allowed scientists to determine the underlying mechanism for the former in the case of Respiratory syncytial virus (RSV) vaccine and have been utilized to design and screen new RSV vaccine candidates. Because some Middle East respiratory syndrome (MERS) and SARS-CoV-1 vaccines have shown evidence of disease enhancement in some animal models, this is a particular concern for SARS-CoV-2 vaccines. To address this challenge, the Coalition for Epidemic Preparedness Innovations (CEPI) and the Brighton Collaboration (BC) Safety Platform for Emergency vACcines (SPEAC) convened a scientific working meeting on March 12 and 13, 2020 of experts in the field of vaccine immunology and coronaviruses to consider what vaccine designs could reduce safety concerns and how animal models and immunological assessments in early clinical trials can help to assess the risk. This report summarizes the evidence presented and provides considerations for safety assessment of COVID-19 vaccine candidates in accelerated vaccine development.

Neutralizing antibody persistence in pediatric travelers from non-JE-endemic countries following vaccination with IXIARO® Japanese encephalitis vaccine: An uncontrolled, open-label phase 3 follow-up study.

BACKGROUND: In an initial study among children from non-Japanese encephalitis (JE)-endemic countries, seroprotection rates remained high 6 months after completion of the primary series with IXIARO®. METHODS: In this open-label follow-up study, a subset of 23 children who received a 2-dose primary series of IXIARO® in the parent study, were evaluated for safety and neutralizing antibody persistence for 36 months. RESULTS: Seroprotection rates (SPRs) remained high but declined from 100% one month after primary immunization to 91.3% at month 7 and 89.5% at month 36. Geometric mean titers (GMTs) declined considerably from 384.1 by day 56-60.8 at month 36. No long-term safety concerns were identified. CONCLUSIONS: The substantial decline in GMT observed in this study, together with previously published data on children vaccinated with IXIARO® support the recommendation for a booster dose in children who remain at risk of JE from 1 year after the primary series of IXIARO®, consistent with the recommendation for adults. CLINICAL TRIAL REGISTRY NUMBER: NCT01246479.

Correction to: Developing vaccines against epidemic-prone emerging infectious diseases.

In the original publication of this article, the author name Richard Hatchett was incorrectly published.

Developing vaccines against epidemic-prone emerging infectious diseases.

Today's world is characterized by increasing population density, human mobility, urbanization, and climate and ecological change. This global dynamic has various effects, including the increased appearance of emerging infectious diseases (EIDs), which pose a growing threat to global health security.Outbreaks of EIDs, like the 2013-2016 Ebola outbreak in West Africa or the current Ebola outbreak in Democratic Republic of the Congo (DRC), have not only put populations in low- and middle-income countries (LMIC) at risk in terms of morbidity and mortality, but they also have had a significant impact on economic growth in affected regions and beyond.The Coalition for Epidemic Preparedness Innovation (CEPI) is an innovative global partnership between public, private, philanthropic, and civil society organizations that was launched as the result of a consensus that a coordinated, international, and intergovernmental plan was needed to develop and deploy new vaccines to prevent future epidemics.CEPI is focusing on supporting candidate vaccines against the World Health Organization (WHO) Blueprint priority pathogens MERS-CoV, Nipah virus, Lassa fever virus, and Rift Valley fever virus, as well as Chikungunya virus, which is on the WHO watch list. The current vaccine portfolio contains a wide variety of technologies, ranging across recombinant viral vectors, nucleic acids, and recombinant proteins. To support and accelerate vaccine development, CEPI will also support science projects related to the development of biological standards and assays, animal models, epidemiological studies, and diagnostics, as well as build capacities for future clinical trials in risk-prone contexts.

Determinants of post-malarial anemia in African children treated with parenteral artesunate.

The pathophysiology of malarial anemia is multifactorial and incompletely understood. We assessed mechanistic and risk factors for post-malarial anemia in Ghanaian and Gabonese children with severe P. falciparum malaria treated with parenteral artesunate followed by an oral artemisinin-combination therapy. We analyzed data from two independent studies in which children were followed on Days 7,14, and 28 after treatment with artesunate. Specific hematological parameters included the presence of hemoglobinopathies and erythropoietin. Presence of once-infected erythrocytes was assessed by flow cytometry in a sub-population. Of 143 children with a geometric mean parasitemia of 116,294/µL (95% CI: 95,574-141,505), 91 (88%) had anemia (Hb < 10 g/dL) at presentation. Hemoglobin increased after Day 7 correlating with increased erythropoiesis through adequate erythropoietin stimulation. 22 children (24%) remained anemic until Day 28. Post-artesunate delayed hemolysis was detected in 7 children (5%) with only minor differences in the dynamics of once-infected erythrocytes. Hyperparasitemia and hemoglobin at presentation were associated with anemia on Day 14. On Day 28 only lower hemoglobin at presentation was associated with anemia. Most children showed an adequate erythropoiesis and recovered from anemia within one month. Post-artesunate delayed hemolysis (PADH) and hyperparasitemia are associated with early malarial anemia and pre-existing anemia is the main determinant for prolonged anemia.

Persistence of Antibodies to 2 Virus-Like Particle Norovirus Vaccine Candidate Formulations in Healthy Adults: 1-Year Follow-up With Memory Probe Vaccination.

BACKGROUND: We previously reported the tolerability and immunogenicity 1 month after intramuscular administration of 2 bivalent virus-like particle (VLP)-based candidate norovirus vaccine formulations in adults. We now describe the persistence of immunity and responses to a memory probe vaccination 1 year later. METHODS: A total of 454 healthy men and women aged 18-49 years in 3 equal groups received placebo (saline) or 15/50 or 50/50 vaccine formulations (ie, 15 or 50 µg of GI.1 genotype VLPs, respectively, and 50 µg of GII.4c VLPs) with MPL and Al(OH)3. Immunogenicity and safety were assessed up to day 365, when 351 participants received a memory probe vaccination of 15 µg each of GI.1 and GII.4c VLPs with Al(OH)3. RESULTS: No safety signals were detected up to 1 year after the first vaccination. Pan-immunoglobulin, immunoglobulin A, and histo-blood group antigen-blocking (HBGA) antibody levels among vaccinees waned but remained higher than levels before vaccination and levels in placebo recipients on days 180 and 365. Memory probe vaccination increased all antibody titers. Levels of HBGA antibodies to GI.1 but not GII.4c were higher after the first vaccination in candidate vaccine groups, compared with those in the placebo group. CONCLUSION: Levels of antibodies to both candidate norovirus VLP formulations persisted above baseline levels for at least 1 year after primary vaccination. HBGA-blocking responses to the memory probe for GI.1 but not GII.4c displayed characteristics of immune memory. CLINICAL TRIALS REGISTRATION: NCT02142504.

A Prospective Study on the Impact and Out-of-Pocket Costs of Dengue Illness in International Travelers.

Although the costs of dengue illness to patients and households have been extensively studied in endemic populations, international travelers have not been the focus of costing studies. As globalization and human travel activities intensify, travelers are increasingly at risk for emerging and reemerging infectious diseases, such as dengue. This exploratory study aims to investigate the impact and out-of-pocket costs of dengue illness among travelers. We conducted a prospective study in adult travelers with laboratory-confirmed dengue and recruited patients at travel medicine clinics in eight different countries from December 2013 to December 2015. Using a structured questionnaire, we collected information on patients and their health-care utilization and out-of-pocket expenditures, as well as income and other financial losses they incurred because of dengue illness. A total of 90 patients participated in the study, most of whom traveled for tourism (74%) and visited countries in Asia (82%). Although 22% reported hospitalization and 32% receiving ambulatory care while traveling, these percentages were higher at 39% and 71%, respectively, after returning home. The out-of-pocket direct and indirect costs of dengue illness were US$421 (SD 744) and US$571 (SD 1,913) per episode, respectively, averaging to a total out-of-pocket cost of US$992 (SD 2,052) per episode. The study findings suggest that international travelers incur important direct and indirect costs because of dengue-related illness. This study is the first to date to investigate the impact and out-of-pocket costs of travel-related dengue illness from the patient's perspective and paves the way for future economic burden studies in this population.

An Exploratory Study of the Salivary Immunoglobulin A Responses to 1 Dose of a Norovirus Virus-Like Particle Candidate Vaccine in Healthy Adults.

As noroviruses are transmitted through the fecal-oral route, we investigated humoral and mucosal (salivary immunoglobulin A [IgA]) immune responses in a phase 2 trial of Takeda's bivalent norovirus virus-like particle (VLP) vaccine candidate in 50 healthy 18- to 49-year-olds. The vaccine had an acceptable tolerability profile and induced rapid, robust humoral immune responses after 1 intramuscular dose of vaccine candidate. Seroresponses were evident 8 days after vaccination as panimmunoglobulin, IgA, and histo-blood group antigen-blocking antibodies against both vaccine GI.1 and GII.4c genotypes. Salivary IgA levels were approximately 1000-fold lower than serum concentrations, and moderately or strongly correlated with the serum IgA titers at all time-points.

Safety and immunogenicity of an inactivated Vero cell_derived Japanese encephalitis vaccine (IXIARO®, JESPECT®) in a pediatric population in JE non-endemic countries: An uncontrolled, open-label phase 3 study.

BACKGROUND: Young travelers to South-East Asia may be at risk for Japanese encephalitis (JE). METHODS: IXIARO® (0.25 ml or 0.5 ml, depending on age) were administrated to 100 travelers aged ≥ 2 months to < 18 years. Solicited AEs were collected for 7 days after each injection, unsolicited adverse events (AEs) for a total of 7 months. JE neutralizing antibodies were assessed in 64 subjects. RESULTS: The most common solicited local AEs were redness (3/12 subjects), induration and tenderness (both 1/12) with 0.25 ml IXIARO®, and tenderness (44/88) and pain (22/88) with 0.5 ml IXIARO®. Common solicited systemic AEs were diarrhea (2/12) and loss of appetite (1/12) with 0.25 ml IXIARO® and muscle pain (27/88) and excessive fatigue (10/88) with 0.5 ml IXIARO®. In total, up to day 56, AEs were reported by 10/12 (83.3%) of subjects who received the 0.25 ml dose and 67/88 (76.1%) of those vaccinated with the 0.5 ml dose. All subjects (62/62; 100%) developed protective levels of JE neutralizing antibodies by Day 56 and 31/34 (91.2%) retained protective titers at Month 7. CONCLUSIONS: IXIARO® was generally well tolerated in children, with an overall AE profile similar to adults. IXIARO® was highly immunogenic in both dose groups.

Safety and Immunogenicity of Different Formulations of Norovirus Vaccine Candidate in Healthy Adults: A Randomized, Controlled, Double-Blind Clinical Trial.

Background: We investigated safety and immunogenicity of 1-2 doses of different bivalent virus-like particle (VLP) norovirus vaccine candidate (NoV) formulations in healthy 18- to 64-year-olds. Methods: On days 1 and 28, participants (n = 420) randomized to 14 equal groups received intramuscular control vaccine (hepatitis A) or 1 of 11 NoV formulations containing varying dosages of GI.1 and GII.4c genotype VLP antigens with aluminum hydroxide [Al(OH)3], and 0 µg, 15 µg, or 50 µg monophosphoryl lipid A (MPL). Immunogenicity was assessed on days 1, 28, 56, 208 and 393. Solicited local and systemic reactions were recorded for 7 days, unsolicited adverse events (AEs) until day 56, and serious AEs throughout the trial. Results: All NoV formulations induced similar increases in pan-immunoglobulin, immunoglobulin A, and histo-blood group binding antigen-blocking antibodies by day 56, mostly after 1 dose, that persisted above baseline to day 393. Higher GI.1 content interfered with GII.4c responses, and responses did not benefit from MPL. Overall reactogenicity consisted of mainly mild injection site pain, headache, and fatigue. No vaccine-related serious AEs were reported. Conclusions: All candidate NoV formulations were well tolerated. Overall, 15 µg GI.1/50 µg GII.4c elicited the best balance of immunogenicity with no clear benefit of MPL, and is the candidate formulation being taken forward in clinical development. Clinical Trials Registration: NCT02038907.