Influenza A(H7N9) Pandemic Preparedness: Assessment of the Breadth of Heterologous Antibody Responses to Emerging Viruses from Multiple Pre-Pandemic Vaccines and Population Immunity.

Influenza A(H7N9) viruses remain as a high pandemic threat. The continued evolution of the A(H7N9) viruses poses major challenges in pandemic preparedness strategies through vaccination. We assessed the breadth of the heterologous neutralizing antibody responses against the 3rd and 5th wave A(H7N9) viruses using the 1st wave vaccine sera from 4 vaccine groups: 1. inactivated vaccine with 2.8 µg hemagglutinin (HA)/dose + AS03A; 2. inactivated vaccine with 5.75 µg HA/dose + AS03A; 3. inactivated vaccine with 11.5 µg HA/dose + MF59; and 4. recombinant virus like particle (VLP) vaccine with 15 µg HA/dose + ISCOMATRIX™. Vaccine group 1 had the highest antibody responses to the vaccine virus and the 3rd/5th wave drifted viruses. Notably, the relative levels of cross-reactivity to the drifted viruses as measured by the antibody GMT ratios to the 5th wave viruses were similar across all 4 vaccine groups. The 1st wave vaccines induced robust responses to the 3rd and Pearl River Delta lineage 5th wave viruses but lower cross-reactivity to the highly pathogenic 5th wave A(H7N9) virus. The population in the United States was largely immunologically naive to the A(H7N9) HA. Seasonal vaccination induced cross-reactive neuraminidase inhibition and binding antibodies to N9, but minimal cross-reactive antibody-dependent cell-mediated cytotoxicity (ADCC) antibodies to A(H7N9).

A Newcastle Disease Virus (NDV) Expressing a Membrane-Anchored Spike as a Cost-Effective Inactivated SARS-CoV-2 Vaccine.

A successful severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine must not only be safe and protective, but must also meet the demand on a global scale at a low cost. Using the current influenza virus vaccine production capacity to manufacture an egg-based inactivated Newcastle disease virus (NDV)/SARS-CoV-2 vaccine would meet that challenge. Here, we report pre-clinical evaluations of an inactivated NDV chimera stably expressing the membrane-anchored form of the spike (NDV-S) as a potent coronavirus disease 2019 (COVID-19) vaccine in mice and hamsters. The inactivated NDV-S vaccine was immunogenic, inducing strong binding and/or neutralizing antibodies in both animal models. More importantly, the inactivated NDV-S vaccine protected animals from SARS-CoV-2 infections. In the presence of an adjuvant, antigen-sparing could be achieved, which would further reduce the cost while maintaining the protective efficacy of the vaccine.

A Newcastle disease virus (NDV) expressing membrane-anchored spike as a cost-effective inactivated SARS-CoV-2 vaccine.

A successful SARS-CoV-2 vaccine must be not only safe and protective but must also meet the demand on a global scale at low cost. Using the current influenza virus vaccine production capacity to manufacture an egg-based inactivated Newcastle disease virus (NDV)/SARS-CoV-2 vaccine would meet that challenge. Here, we report pre-clinical evaluations of an inactivated NDV chimera stably expressing the membrane-anchored form of the spike (NDV-S) as a potent COVID-19 vaccine in mice and hamsters. The inactivated NDV-S vaccine was immunogenic, inducing strong binding and/or neutralizing antibodies in both animal models. More importantly, the inactivated NDV-S vaccine protected animals from SARS-CoV-2 infections or significantly attenuated SARS-CoV-2 induced disease. In the presence of an adjuvant, antigen-sparing could be achieved, which would further reduce the cost while maintaining the protective efficacy of the vaccine.

Assessment of an optimized manufacturing process for inactivated quadrivalent influenza vaccine: a phase III, randomized, double-blind, safety and immunogenicity study in children and adults.

BACKGROUND: GSK has modified the licensed monovalent bulk manufacturing process for its split-virion inactivated quadrivalent influenza vaccine (IIV4) to harmonize the process among different strains, resulting in an increased number of finished vaccine doses, while compensating for the change from inactivated trivalent influenza vaccine (IIV3) to IIV4. To confirm the manufacturing changes do not alter the profile of the vaccine, a clinical trial was conducted to compare IIV4 made by the currently licensed process with a vaccine made by the new (investigational) process (IIV4-I). The main objectives were to compare the reactogenicity and safety of IIV4-I versus IIV4 in all age groups, and to demonstrate the non-inferiority of the hemagglutination-inhibition (HI) antibody responses based on the geometric mean titer ratio of IIV4-I versus IIV4 in children. METHODS: The Phase III, randomized, double-blind, multinational study included three cohorts: adults (18-49 years; N = 120), children (3-17 years; N = 821), and infants (6-35 months; N = 940). Eligible subjects in each cohort were randomized 1:1 to receive IIV4-I or IIV4. Both vaccines contained 15 µg of hemagglutinin antigen for each of the four seasonal virus strains. Adults and vaccine-primed children received one dose of vaccine, and vaccine-unprimed children received two doses of vaccine 28 days apart. All children aged ≥9 years were considered to be vaccine-primed and received one dose of vaccine. RESULTS: The primary immunogenicity objective of the study was met in demonstrating immunogenic non-inferiority of IIV4-I versus IIV4 in children. The IIV4-I was immunogenic against all four vaccine strains in each age cohort. The reactogenicity and safety profile of IIV4-I was similar to IIV4 in each age cohort, and there was no increase in the relative risk of fever (≥38 °C) with IIV4-I versus IIV4 within the 7-day post-vaccination period in infants (1.06; 95% Confidence Interval: 0.75, 1.50; p = 0.786). CONCLUSIONS: The study demonstrated that in adults, children, and infants, the IIV4-I made using an investigational manufacturing process was immunogenic with a reactogenicity and safety profile that was similar to licensed IIV4. These results support that the investigational process used to manufacture IIV4-I is suitable to replace the current licensed process. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02207413 ; trial registration date: August 4, 2014.

Clinical development and regulatory points for consideration for second-generation live attenuated dengue vaccines.

Licensing and decisions on public health use of a vaccine rely on a robust clinical development program that permits a risk-benefit assessment of the product in the target population. Studies undertaken early in clinical development, as well as well-designed pivotal trials, allow for this robust characterization. In 2012, WHO published guidelines on the quality, safety and efficacy of live attenuated dengue tetravalent vaccines. Subsequently, efficacy and longer-term follow-up data have become available from two Phase 3 trials of a dengue vaccine, conducted in parallel, and the vaccine was licensed in December 2015. The findings and interpretation of the results from these trials released both before and after licensure have highlighted key complexities for tetravalent dengue vaccines, including concerns vaccination could increase the incidence of dengue disease in certain subpopulations. This report summarizes clinical and regulatory points for consideration that may guide vaccine developers on some aspects of trial design and facilitate regulatory review to enable broader public health recommendations for second-generation dengue vaccines.

Cost-effectiveness of childhood hepatitis A vaccination in Argentina: a second dose is warranted.

OBJECTIVES: To investigate the cost-effectiveness of childhood vaccination against hepatitis A in the five geographic regions of Argentina, and to determine whether adding a second dose to the current one-dose schedule would provide health gains justifying its added cost. METHODS: A Markov model was used to consider four immunization options for the 2005 birth cohort: (1) no vaccination; (2) vaccination at 12 months of age, (3) vaccinations at 12 and 72 months of age; or (4) vaccinations at 12 and 18 months of age. Hepatitis A costs and consequences were predicted over 50 years. The cost-effectiveness of first and second vaccine doses was assessed through a range of vaccine prices and assumptions regarding the duration of vaccine protection. Costs and health gains (measured in quality-adjusted life years) were adjusted to present values using a 3% annual discount rate. RESULTS: The one-dose vaccination policy is predicted to reduce each birth cohort member's 50-year probability of overt hepatitis A from 7.2% to 4.1%. A second dose would reduce the probability to between 2.0% and 2.2%. Vaccination at 12 months of age, at 12 and 72 months, or at 12 and 18 months would reduce cases among personal contacts by 82%, 87%, and 92%, respectively. The first vaccine dose would meet accepted standards of cost-effectiveness in each region, and reduce costs in the Northeast, Central, and South regions. Adding a second dose at age 18 months would be cost-effective in each region, and further reduce costs in the Cuyo region. If the duration of protection with one dose is less than anticipated, the second dose would be more cost-effective. CONCLUSIONS: Greater health gains are derived from the first than second hepatitis A vaccine dose. However, this analysis supports the cost-effectiveness of providing both first and second doses to Argentina's children.

Economic and health burden of rotavirus gastroenteritis for the 2003 birth cohort in eight Latin American and Caribbean countries.

OBJECTIVE: To estimate the health and economic burden of rotavirus gastroenteritis in hospital and outpatient settings in eight Latin American and Caribbean countries (Argentina, Brazil, Chile, Dominican Republic, Honduras, Mexico, Panama, and Venezuela). METHODS: An economic model was constructed using epidemiological data from published articles, national health administration studies, and country-specific cost estimates. For each of the eight countries, the model estimated the rotavirus outcomes for the 2003 birth cohort during the first five years of life. The main outcome measures included health care costs, transportation costs, lost wages, and disease burden expressed in disability-adjusted life years. Estimates were expressed in 2003 US dollars. All future costs and disability-adjusted life year estimates were discounted at a rate of 3%. Sensitivity analyses evaluated the impact of specific variables on the medical cost of treating rotavirus. RESULTS: For every 1,000 children born during 2003 in the eight Latin American and Caribbean countries studied here, we estimated that rotavirus gastroenteritis would result in an average of 246 outpatient visits, 24 hospitalizations, 0.6 deaths, and 7,971 US dollars in direct medical costs during their first five years of life. The incidence of rotavirus-associated outpatient visits and the cost of outpatient visits were predicted to have the largest impact on the total medical cost per child. CONCLUSIONS: Rotavirus gastroenteritis is likely to result in substantial disease and economic burden to health systems in Latin American and Caribbean countries, and the foreseeable burden should be an important consideration in evaluating the cost-effectiveness of vaccination.

Potential cost-effectiveness of vaccination for rotavirus gastroenteritis in eight Latin American and Caribbean countries.

OBJECTIVES: To estimate the costs, benefits and cost-effectiveness of vaccination for rotavirus gastroenteritis in eight Latin American and Caribbean countries: Argentina, Brazil, Chile, the Dominican Republic, Honduras, Mexico, Panama, and Venezuela. METHODS: An economic model was constructed to estimate the cost-effectiveness of vaccination from the health care system perspective, using national administrative and published epidemiological evidence, country-specific cost estimates, and vaccine efficacy data. The model was applied to the first five years of life for the 2003 birth cohort in each country. The main health outcome was the disability-adjusted life year (DALY), and the main summary measure was the incremental cost per DALY averted. A 3% discount rate was used for all predicted costs and benefits. Sensitivity analyses evaluated the impact of uncertainty regarding key variables on cost-effectiveness estimates. RESULTS: According to the estimates obtained with the economic model, vaccination would prevent more than 65% of the medical visits, deaths, and treatment costs associated with rotavirus gastroenteritis in the eight countries analyzed here. At a cost of US$ 24 per course (for a two-dose vaccine), the incremental cost-effectiveness ratio ranged from 269 US dollars/DALY in Honduras to 10,656 US dollars/DALY in Chile. Cost-effectiveness ratios were sensitive to assumptions about vaccine price, mortality, and vaccine efficacy. CONCLUSIONS: Vaccination would effectively reduce the disease burden and health care costs of rotavirus gastroenteritis in the Latin American and Caribbean countries analyzed here. From the health care system perspective, universal vaccination of infants is predicted to be cost-effective, based on current standards.

Cost-effectiveness of childhood hepatitis A vaccination in Argentina: a second dose is warranted / Efectividad en función del costo de la vacunación infantil contra la hepatitis A en Argentina: se justifica una segunda dosis

OBJECTIVES: To investigate the cost-effectiveness of childhood vaccination against hepatitis A in the five geographic regions of Argentina, and to determine whether adding a second dose to the current one-dose schedule would provide health gains justifying its added cost. METHODS: A Markov model was used to consider four immunization options for the 2005 birth cohort: (1) no vaccination; (2) vaccination at 12 months of age, (3) vaccinations at 12 and 72 months of age; or (4) vaccinations at 12 and 18 months of age. Hepatitis A costs and consequences were predicted over 50 years. The cost-effectiveness of first and second vaccine doses was assessed through a range of vaccine prices and assumptions regarding the duration of vaccine protection. Costs and health gains (measured in quality-adjusted life years) were adjusted to present values using a 3 percent annual discount rate. RESULTS: The one-dose vaccination policy is predicted to reduce each birth cohort member's 50-year probability of overt hepatitis A from 7.2 percent to 4.1 percent. A second dose would reduce the probability to between 2.0 percent and 2.2 percent. Vaccination at 12 months of age, at 12 and 72 months, or at 12 and 18 months would reduce cases among personal contacts by 82 percent, 87 percent, and 92 percent, respectively. The first vaccine dose would meet accepted standards of cost-effectiveness in each region, and reduce costs in the Northeast, Central, and South regions. Adding a second dose at age 18 months would be cost-effective in each region, and further reduce costs in the Cuyo region. If the duration of protection with one dose is less than anticipated, the second dose would be more cost-effective. CONCLUSIONS: Greater health gains are derived from the first than second hepatitis A vaccine dose. However, this analysis supports the cost-effectiveness of providing both first and second doses to Argentina's children.

OBJETIVOS: Investigar la efectividad en función del costo de la vacunación infantil contra la hepatitis A en las cinco regiones de Argentina y determinar si la adición de una segunda dosis al esquema actual de una dosis aumentaría los beneficios a la salud y si estos justificarían el costo adicional. MÉTODOS: Se empleó el modelo de Markov para valorar cuatro opciones de vacunación para la cohorte nacida en el año 2005: 1) no vacunar; 2) vacunar a los 12 meses de edad; 3) vacunar a los 12 y a los 72 meses; y 4) vacunar a los 12 y a los 18 meses de edad. Se estimaron el costo y las consecuencias de la enfermedad a 50 años. La efectividad en función del costo de la primera y la segunda dosis de la vacuna se calculó a partir de varios precios de la vacuna e hipótesis acerca de la duración de la protección. Los costos y los beneficios para la salud (medidos en años de vida ajustados por la calidad de vida) se ajustaron por los valores actuales utilizando una tasa de descuento anual de 3 por ciento. RESULTADOS: Se estima que la política de vacunación con una dosis reduciría la probabilidad de cada miembro de la cohorte de padecer hepatitis A sintomática en 50 años de 7,2 por ciento a 4,1 por ciento. Una segunda dosis reduciría esa probabilidad a 2,0 por ciento-2,2 por ciento. La vacunación a los 12 meses de edad, a los 12 y a los 72 meses, o a los 12 y a los 18 meses reduciría el número de casos entre los contactos personales en 82 por ciento, 87 por ciento y 92 por ciento, respectivamente. La primera dosis de la vacuna satisfaría los estándares aceptados de efectividad en función del costo en todas las regiones del país y reduciría los costos en las regiones Nordeste, Central y Sur. La aplicación de una segunda dosis a los 18 meses resultaría efectiva en función del costo en todas las regiones y reduciría adicionalmente los costos en la región de Cuyo. Si la duración de la protección con una dosis fuera menor de la esperada, la segunda dosis tendría una mayor efectividad en función del costo. Conclusiones. La primera dosis de la vacuna contra la hepatitis A genera mayores beneficios a la salud que la segunda. Sin embargo, este análisis sustenta la efectividad en función del costo de aplicar ambas dosis a los niños en Argentina.

Economic and health burden of rotavirus gastroenteritis for the 2003 birth cohort in eight Latin American and Caribbean countries / Carga económica y de morbilidad de la gastroenteritis por rotavirus en la cohorte de nacidos en 2003 en ocho países de América Latina y el Caribe

OBJECTIVE: To estimate the health and economic burden of rotavirus gastroenteritis in hospital and outpatient settings in eight Latin American and Caribbean countries (Argentina, Brazil, Chile, Dominican Republic, Honduras, Mexico, Panama, and Venezuela). METHODS: An economic model was constructed using epidemiological data from published articles, national health administration studies, and country-specific cost estimates. For each of the eight countries, the model estimated the rotavirus outcomes for the 2003 birth cohort during the first five years of life. The main outcome measures included health care costs, transportation costs, lost wages, and disease burden expressed in disability-adjusted life years. Estimates were expressed in 2003 US dollars. All future costs and disability-adjusted life year estimates were discounted at a rate of 3 percent. Sensitivity analyses evaluated the impact of specific variables on the medical cost of treating rotavirus. RESULTS: For every 1 000 children born during 2003 in the eight Latin American and Caribbean countries studied here, we estimated that rotavirus gastroenteritis would result in an average of 246 outpatient visits, 24 hospitalizations, 0.6 deaths, and US$ 7 971 in direct medical costs during their first five years of life. The incidence of rotavirus-associated outpatient visits and the cost of outpatient visits were predicted to have the largest impact on the total medical cost per child. CONCLUSIONS: Rotavirus gastroenteritis is likely to result in substantial disease and economic burden to health systems in Latin American and Caribbean countries, and the foreseeable burden should be an important consideration in evaluating the cost-effectiveness of vaccination.

OBJETIVO: Estimar la carga económica y de morbilidad de la gastroenteritis por rotavirus en hospitales y servicios ambulatorios de ocho países de América Latina y el Caribe (Argentina, Brasil, Chile, Honduras, México, Panamá, República Dominicana y Venezuela). MÉTODOS: Se elaboró un modelo económico a partir de datos epidemiológicos de artículos publicados, estudios de autoridades sanitarias nacionales y los estimados de costos específicos de cada país. El modelo calculó las consecuencias de la infección por rotavirus en los primeros cinco años de vida de la cohorte de nacidos en 2003 en cada uno de los ocho países estudiados. Las principales medidas de valoración fueron los costos de la atención sanitaria, los costos de transportación, los salarios perdidos y la carga de morbilidad expresada en años de vida ajustados por discapacidad. Los estimados se expresaron en dólares estadounidenses del año 2003. Se empleó una tasa de descuento de 3 por ciento para los cálculos de costos y años de vida ajustados por discapacidad de los años siguientes. El impacto de las variables específicas sobre los costos clínicos del tratamiento de la infección por rotavirus se realizó mediante análisis de sensibilidad. RESULTADOS: Se estimó que durante los primeros cinco años de vida, la gastroenteritis por rotavirus provoca en promedio 246 consultas externas, 24 hospitalizaciones, 0,6 muertes y gastos médicos directos por US$ 7 971,00 por cada 1 000 niños nacidos en 2003 en los ocho países estudiados de América Latina y el Caribe. Se prevé que la frecuencia de visitas médicas asociadas con la infección por rotavirus y los costos por consultas externas tengan el mayor impacto en los costos clínicos totales por niño. CONCLUSIONES: La gastroenteritis por rotavirus puede representar una considerable carga económica y de morbilidad para los sistemas sanitarios de los países de América Latina y el Caribe. Se debe prestar una especial atención a la carga previsible al evaluar la efectividad en función del costo de la vacunación contra rotavirus.

Potential cost-effectiveness of vaccination for rotavirus gastroenteritis in eight Latin American and Caribbean countries / Efectividad potencial en función del costo de la vacunación contra la gastroenteritis por rotavirus en ocho países de América Latina y el Caribe

OBJECTIVES: To estimate the costs, benefits and cost-effectiveness of vaccination for rotavirus gastroenteritis in eight Latin American and Caribbean countries: Argentina, Brazil, Chile, the Dominican Republic, Honduras, Mexico, Panama, and Venezuela. METHODS: An economic model was constructed to estimate the cost-effectiveness of vaccination from the health care system perspective, using national administrative and published epidemiological evidence, country-specific cost estimates, and vaccine efficacy data. The model was applied to the first five years of life for the 2003 birth cohort in each country. The main health outcome was the disability-adjusted life year (DALY), and the main summary measure was the incremental cost per DALY averted. A 3 percent discount rate was used for all predicted costs and benefits. Sensitivity analyses evaluated the impact of uncertainty regarding key variables on cost-effectiveness estimates. RESULTS: According to the estimates obtained with the economic model, vaccination would prevent more than 65 percent of the medical visits, deaths, and treatment costs associated with rotavirus gastroenteritis in the eight countries analyzed here. At a cost of US$ 24 per course (for a two-dose vaccine), the incremental cost-effectiveness ratio ranged from US$ 269/DALY in Honduras to US$ 10 656/DALY in Chile. Cost-effectiveness ratios were sensitive to assumptions about vaccine price, mortality, and vaccine efficacy. CONCLUSIONS: Vaccination would effectively reduce the disease burden and health care costs of rotavirus gastroenteritis in the Latin American and Caribbean countries analyzed here. From the health care system perspective, universal vaccination of infants is predicted to be cost-effective, based on current standards.

OBJETIVOS: Estimar los costos, los beneficios y la efectividad en función del costo de la vacunación contra la gastroenteritis por rotavirus en ocho países de América Latina y el Caribe: Argentina, Brasil, Chile, Honduras, México, Panamá, República Dominicana y Venezuela. MÉTODOS: Se elaboró un modelo económico para estimar la efectividad en función del costo de la vacunación, desde la perspectiva del sistema de salud, a partir de las constancias epidemiológicas nacionales oficiales y publicadas, los estimados de costos específicos de cada país y los datos de eficacia de la vacuna. El modelo se aplicó a los primeros cinco años de vida de la cohorte de nacidos en 2003 en cada uno de esos países. La principal medida de salud fueron los años de vida ajustados por discapacidad (AVAD) y la principal medida sintética fue el costo incremental por AVAD evitado. Se empleó una tasa de descuento de 3 por ciento para el pronóstico de los costos y beneficios. El impacto de la incertidumbre relacionada con las variables clave sobre la efectividad en función del costo se realizó mediante el análisis de sensibilidad. RESULTADOS: Según los estimados obtenidos mediante el modelo económico, la vacunación podría evitar más de 65 por ciento de las consultas médicas, de las muertes y del costo de tratamiento asociados con la gastroenteritis por rotavirus en los ocho países analizados. Con un costo total de US$ 24,00 (por las dos dosis de la vacuna), la razón incremental de la efectividad en función del costo varió entre US$ 269/AVAD en Honduras y US$ 10 656/AVAD en Chile. Las razones de la efectividad en función del costo fueron sensibles a las diversas hipótesis sobre el precio de la vacuna, la mortalidad y la eficacia de la vacuna. CONCLUSIONES: La vacunación permitiría reducir eficazmente la carga de morbilidad y los costos de la atención sanitaria de la gastroenteritis por rotavirus en los países analizados de América Latina y el Caribe. Desde la perspectiva de los sistemas de salud, se prevé que la vacunación universal de todos los niños será efectiva en función del costo, según los estándares vigentes en la actualidad.

Cost-effectiveness of universal childhood hepatitis A vaccination in Chile.

Hepatitis A is an important public health problem in Chile. Childhood vaccination has reduced hepatitis A rates in several countries, prompting this evaluation of its cost-effectiveness in Chile. Using a Markov model, we project mass vaccination would reduce hepatitis A cases among birth cohort members and their personal contacts >80%. Vaccination costs of US dollars 5.3-6.4 million would be offset by US dollars 9.2-9.4 million reductions in disease costs. Further, approximately 70 fatal infections would be averted and >4600 quality-adjusted life years would be saved. This analysis supports the cost-effectiveness of universal childhood hepatitis A vaccination in Chile.