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Many aspects of Controlled Human Infection Models (CHIMs, also known as human challenge studies and human infection studies) have been discussed extensively, including Good Manufacturing Practice (GMP) production of the challenge agent, CHIM ethics, environmental safety in CHIM, recruitment, community engagement, advertising and incentives, pre-existing immunity, and clinical, immunological, and microbiological endpoints. The fourth CHIM meeting focused on regulation of CHIM studies, bringing together scientists and regulators from high-, middle-, and low-income countries, to discuss barriers and hurdles in CHIM regulation. Valuable initiatives for regulation of CHIMs have already been undertaken but further capacity building remains essential. The Wellcome Considerations document is a good starting point for further discussions.
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The urgency to develop vaccines against Covid-19 is putting pressure on the long and expensive development timelines that are normally required for development of lifesaving vaccines. There is a unique opportunity to take advantage of new technologies, the smart and flexible design of clinical trials, and evolving regulatory science to speed up vaccine development against Covid-19 and transform vaccine development altogether.
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Vacunas contra la COVID-19/uso terapéutico , COVID-19/prevención & control , Aprobación de Drogas , Biología de Sistemas/métodos , COVID-19/inmunología , Humanos , Aprendizaje Automático , Salud Pública/métodos , SARS-CoV-2/inmunología , Vacunología/métodosRESUMEN
BACKGROUND: Several economic obstacles can deter the development and use of vaccines. This can lead to limited product options for some diseases, delays in new product development, and inequitable access to vaccines. Although seemingly distinct, these obstacles are actually interrelated and therefore need to be addressed through a single over-arching strategy encompassing all stakeholders. METHODS: To help overcome these obstacles, we propose a new approach, the Full Value of Vaccines Assessments (FVVA) framework, to guide the assessment and communication of the value of a vaccine. The FVVA framework is designed to facilitate alignment across key stakeholders and to enhance decision-making around investment in vaccine development, policy-making, procurement, and introduction, particularly for vaccines intended for use in low- and middle-income countries. RESULTS: The FVVA framework has three key elements. First, to enhance assessment, existing value-assessment methods and tools are adapted to include broader benefits of vaccines as well as opportunity costs borne by stakeholders. Second, to improve decision-making, a deliberative process is required to recognize the agency of stakeholders and to ensure country ownership of decision-making and priority setting. Third, the FVVA framework provides a consistent and evidence-based approach that facilitates communication about the full value of vaccines, helping to enhance alignment and coordination across diverse stakeholders. CONCLUSIONS: The FVVA framework provides guidance for stakeholders organizing global-level efforts to promote investment in vaccines that are priorities for LMICs. By providing a more holistic view of the benefits of vaccines, its application also has the potential to encourage greater take-up by countries, thereby leading to more sustainable and equitable impacts of vaccines and immunization programmes.
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Vacunas , Humanos , Vacunación , Formulación de Políticas , Países en Desarrollo , Programas de InmunizaciónRESUMEN
Vaccine development and implementation decisions need to be guided by accurate and robust burden of disease data. We developed an innovative systematic framework outlining the properties of such data that are needed to advance vaccine development and evaluation, and prioritize research and surveillance activities. We focus on 4 objectives-advocacy, regulatory oversight and licensure, policy and post-licensure evaluation, and post-licensure financing-and identify key stakeholders and specific requirements for burden of disease data aligned with each objective. We apply this framework to group A Streptococcus, a pathogen with an underrecognized global burden, and give specific examples pertinent to 8 clinical endpoints. This dynamic framework can be adapted for any disease with a vaccine in development and can be updated as vaccine candidates progress through clinical trials. This framework will also help with research and innovation priority setting of the Immunization Agenda 2030 (IA2030) and accelerate development of future vaccines.
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Infecciones Estreptocócicas , Vacunas Estreptocócicas , Costo de Enfermedad , Humanos , Infecciones Estreptocócicas/epidemiología , Infecciones Estreptocócicas/prevención & control , Streptococcus pyogenes , Desarrollo de VacunasRESUMEN
Peter Figueroa and co-authors advocate for equity in the worldwide provision of COVID-19 vaccines.
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Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/uso terapéutico , COVID-19/prevención & control , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , COVID-19/inmunología , Salud Global , HumanosRESUMEN
The development of effective malaria vaccines is hampered by incomplete understanding of the immunological correlates of protective immunity. Recently, the moderate clinical efficacy of the Plasmodium falciparum circumsporozoite protein (CSP)-based RTS,S/AS01E vaccine in phase 3 studies highlighted the urgency to design and test more efficacious next-generation malaria vaccines. In this study, we report that immunization with recombinant CSP from Plasmodium yoelii (rPyCSP), when delivered in Montanide ISA 51, induced sterilizing immunity against sporozoite challenge in C57BL/6 and BALB/c strains of mice. This immunity was antibody dependent, as evidenced by the complete loss of immunity in B-cell-knockout (KO) mice and by the ability of immune sera to neutralize sporozoite infectivity in mice. Th2-type isotype IgG1 antibody levels were associated with protective immunity. The fact that immunized gamma interferon (IFN-γ)-KO mice and wild-type (WT) mice have similar levels of protective immunity and the absence of IFN-γ-producing CD4+ and CD8+ T cells in protected mice, as shown by flow cytometry, indicate that the immunity is IFN-γ independent. Protection against sporozoite challenge correlated with higher frequencies of CD4+ T cells that express interleukin-2 (IL-2), IL-4, and tumor necrosis factor alpha (TNF-α). In the RTS,S study, clinical immunity was associated with higher IgG levels and frequencies of IL-2- and TNF-α-producing CD4+ T cells. The other hallmarks of immunity in our study included an increased number of follicular B cells but a loss in follicular T helper cells. These results provide an excellent model system to evaluate the efficacy of novel adjuvants and vaccine dosage and determine the correlates of immunity in the search for superior malaria vaccine candidates.
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Anticuerpos Antiprotozoarios/biosíntesis , Inmunoglobulina G/biosíntesis , Vacunas contra la Malaria/biosíntesis , Malaria/prevención & control , Plasmodium yoelii/inmunología , Proteínas Protozoarias/administración & dosificación , Adyuvantes Inmunológicos/administración & dosificación , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/parasitología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/parasitología , Femenino , Inmunización , Inmunogenicidad Vacunal , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-2/genética , Interleucina-2/inmunología , Interleucina-4/genética , Interleucina-4/inmunología , Malaria/genética , Malaria/inmunología , Malaria/parasitología , Vacunas contra la Malaria/administración & dosificación , Manitol/administración & dosificación , Manitol/análogos & derivados , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ácidos Oléicos/administración & dosificación , Oligodesoxirribonucleótidos/administración & dosificación , Proteínas Protozoarias/genética , Proteínas Protozoarias/inmunología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , Vacunas de SubunidadRESUMEN
Group A Streptococcus (GAS) infections result in a considerable underappreciated burden of acute and chronic disease globally. A 2018 World Health Assembly resolution calls for better control and prevention. Providing guidance on global health research needs is an important World Health Organization (WHO) activity, influencing prioritization of investments. Here, the role, status, and directions in GAS vaccines research are discussed. WHO preferred product characteristics and a research and development technology roadmap, briefly presented, offer an actionable framework for vaccine development to regulatory and policy decision making, availability, and use. GAS vaccines should be considered for global prevention of the range of clinical manifestations and associated antibiotic use. Impediments related to antigen diversity, safety concerns, and the difficulty to establish vaccine efficacy against rheumatic heart disease are discussed. Demonstration of vaccine efficacy against pharyngitis and skin infections constitutes a key near-term strategic goal. Investments and collaborative partnerships to diversify and advance vaccine candidates are needed.
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Investigación Biomédica , Salud Global , Infecciones Estreptocócicas/prevención & control , Vacunas Estreptocócicas , Organización Mundial de la Salud , Costo de Enfermedad , Humanos , Formulación de Políticas , Streptococcus pyogenes/inmunologíaRESUMEN
BACKGROUND: The candidate malaria vaccine RTS,S/AS01 is being evaluated in order to inform a decision regarding its inclusion in routine vaccination schedules. METHODS: We conducted 7 years of follow-up in children who had been randomly assigned, at 5 to 17 months of age, to receive three doses of either the RTS,S/AS01 vaccine or a rabies (control) vaccine. The end point was clinical malaria (temperature of ≥37.5°C and infection with Plasmodium falciparum of >2500 parasites per cubic millimeter). In an analysis that was not prespecified, the malaria exposure of each child was estimated with the use of information on the prevalence of malaria among residents within a 1-km radius of the child's home. Vaccine efficacy was defined as 1 minus the hazard ratio or the incidence-rate ratio, multiplied by 100, in the RTS,S/AS01 group versus the control group. RESULTS: Over 7 years of follow-up, we identified 1002 episodes of clinical malaria among 223 children randomly assigned to the RTS,S/AS01 group and 992 episodes among 224 children randomly assigned to the control group. The vaccine efficacy, as assessed by negative binomial regression, was 4.4% (95% confidence interval [CI], -17.0 to 21.9; P=0.66) in the intention-to-treat analysis and 7.0% (95% CI, -14.5 to 24.6; P=0.52) in the per-protocol analysis. Vaccine efficacy waned over time (P=0.006 for the interaction between vaccination and time), including negative efficacy during the fifth year among children with higher-than-average exposure to malaria parasites (intention-to-treat analysis: -43.5%; 95% CI, -100.3 to -2.8 [P=0.03]; per-protocol analysis: -56.8%; 95% CI, -118.7 to -12.3 [P=0.008]). CONCLUSIONS: A three-dose vaccination with RTS,S/AS01 was initially protective against clinical malaria, but this result was offset by rebound in later years in areas with higher-than-average exposure to malaria parasites. (Funded by the PATH Malaria Vaccine Initiative and others; ClinicalTrials.gov number, NCT00872963.).
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Vacunas contra la Malaria/inmunología , Malaria Falciparum/prevención & control , Plasmodium falciparum , Vacunas Sintéticas/inmunología , Conjuntos de Datos como Asunto , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Lactante , Análisis de Intención de Tratar , Vacunas contra la Malaria/efectos adversos , Malaria Falciparum/epidemiología , Malaria Falciparum/inmunología , Masculino , Parasitemia , Plasmodium falciparum/inmunología , Plasmodium falciparum/aislamiento & purificación , Modelos de Riesgos Proporcionales , Resultado del Tratamiento , Vacunas Sintéticas/efectos adversosAsunto(s)
Países en Desarrollo/economía , Desarrollo de Medicamentos/economía , Desarrollo de Medicamentos/tendencias , Vacunas/administración & dosificación , Vacunas/economía , Niño , Seguro de Costos Compartidos/economía , Industria Farmacéutica/economía , Salud Global/economía , Salud Global/tendencias , Humanos , Vacunas contra la Malaria/administración & dosificación , Vacunas contra la Malaria/economía , Participación de los Interesados , Vacunación/economía , Vacunación/tendencias , Vacunas/provisión & distribuciónRESUMEN
Achieving a malaria-free world presents exciting scientific challenges as well as overwhelming health, equity, and economic benefits. WHO and countries are setting ambitious goals for reducing the burden and eliminating malaria through the "Global Technical Strategy" and 21 countries are aiming to eliminate malaria by 2020. The commitment to achieve these targets should be celebrated. However, the need for innovation to achieve these goals, sustain elimination, and free the world of malaria is greater than ever. Over 180 experts across multiple disciplines are engaged in the Malaria Eradication Research Agenda (malERA) Refresh process to address problems that need to be solved. The result is a research and development agenda to accelerate malaria elimination and, in the longer term, transform the malaria community's ability to eradicate it globally.
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Investigación Biomédica/métodos , Erradicación de la Enfermedad/métodos , Malaria/epidemiología , Malaria/prevención & control , Animales , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Investigación Biomédica/tendencias , Salud Global/tendencias , Humanos , Control de Mosquitos/tendencias , Plasmodium vivax/efectos de los fármacosRESUMEN
BACKGROUND: Plasmodium falciparum prevalence (PfPR) is a widely used metric for assessing malaria transmission intensity. This study was carried out concurrently with the RTS,S/AS01 candidate malaria vaccine Phase III trial and estimated PfPR over ≤ 4 standardized cross-sectional surveys. METHODS: This epidemiology study (NCT01190202) was conducted in 8 sites from 6 countries (Burkina Faso, Gabon, Ghana, Kenya, Malawi, and Tanzania), between March 2011 and December 2013. Participants were enrolled in a 2:1:1 ratio according to age category: 6 months-4 years, 5-19 years, and ≥ 20 years, respectively, per year and per centre. All sites carried out surveys 1-3 while survey 4 was conducted only in 3 sites. Surveys were usually performed during the peak malaria parasite transmission season, in one home visit, when medical history and malaria risk factors/prevention measures were collected, and a blood sample taken for rapid diagnostic test, microscopy, and haemoglobin measurement. PfPR was estimated by site and age category. RESULTS: Overall, 6401 (survey 1), 6411 (survey 2), 6400 (survey 3), and 2399 (survey 4) individuals were included in the analyses. In the 6 months-4 years age group, the lowest prevalence (assessed using microscopy) was observed in 2 Tanzanian centres (4.6% for Korogwe and 9.95% for Bagamoyo) and Lambaréné, Gabon (6.0%), while the highest PfPR was recorded for Nanoro, Burkina Faso (52.5%). PfPR significantly decreased over the 3 years in Agogo (Ghana), Kombewa (Kenya), Lilongwe (Malawi), and Bagamoyo (Tanzania), and a trend for increased PfPR was observed over the 4 surveys for Kintampo, Ghana. Over the 4 surveys, for all sites, PfPR was predominantly higher in the 5-19 years group than in the other age categories. Occurrence of fever and anaemia was associated with high P. falciparum parasitaemia. Univariate analyses showed a significant association of anti-malarial treatment in 4 surveys (odds ratios [ORs]: 0.52, 0.52, 0.68, 0.41) and bed net use in 2 surveys (ORs: 0.63, 0.68, 1.03, 1.78) with lower risk of malaria infection. CONCLUSION: Local PfPR differed substantially between sites and age groups. In children 6 months-4 years old, a significant decrease in prevalence over the 3 years was observed in 4 out of the 8 study sites. Trial registration Clinical Trials.gov identifier: NCT01190202:NCT. GSK Study ID numbers: 114001.
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Malaria Falciparum/epidemiología , Malaria Falciparum/prevención & control , Plasmodium falciparum/aislamiento & purificación , Adolescente , Adulto , África del Sur del Sahara/epidemiología , Anciano , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Prevalencia , Adulto JovenRESUMEN
BACKGROUND: Three full doses of RTS,S/AS01 malaria vaccine provides partial protection against controlled human malaria parasite infection (CHMI) and natural exposure. Immunization regimens, including a delayed fractional third dose, were assessed for potential increased protection against malaria and immunologic responses. METHODS: In a phase 2a, controlled, open-label, study of healthy malaria-naive adults, 16 subjects vaccinated with a 0-, 1-, and 2-month full-dose regimen (012M) and 30 subjects who received a 0-, 1-, and 7-month regimen, including a fractional third dose (Fx017M), underwent CHMI 3 weeks after the last dose. Plasmablast heavy and light chain immunoglobulin messenger RNA sequencing and antibody avidity were evaluated. Protection against repeat CHMI was evaluated after 8 months. RESULTS: A total of 26 of 30 subjects in the Fx017M group (vaccine efficacy [VE], 86.7% [95% confidence interval [CI], 66.8%-94.6%]; P < .0001) and 10 of 16 in the 012M group (VE, 62.5% [95% CI, 29.4%-80.1%]; P = .0009) were protected against infection, and protection differed between schedules (P = .040, by the log rank test). The fractional dose boosting increased antibody somatic hypermutation and avidity and sustained high protection upon rechallenge. DISCUSSIONS: A delayed third fractional vaccine dose improved immunogenicity and protection against infection. Optimization of the RTS,S/AS01 immunization regimen may lead to improved approaches against malaria. CLINICAL TRIALS REGISTRATION: NCT01857869.
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Esquemas de Inmunización , Vacunas contra la Malaria/administración & dosificación , Vacunas contra la Malaria/inmunología , Malaria/prevención & control , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/inmunología , Adolescente , Adulto , Anticuerpos Antiprotozoarios/biosíntesis , Anticuerpos Antiprotozoarios/inmunología , Afinidad de Anticuerpos , Femenino , Humanos , Cadenas Pesadas de Inmunoglobulina/biosíntesis , Cadenas Ligeras de Inmunoglobulina/biosíntesis , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Both Clostridium difficile and Staphylococcus aureus asymptomatically colonize a significant percentage of humans, particularly during the first year of life. The epidemiology of both has been and continues to be quite dynamic; presently, we are in the midst of epidemics of infections by C. difficile and S. aureus. These ancient microbes are now armed with more potent virulence factors, which have extended their reach from the hospital into community settings, and from the elderly and debilitated hosts into the younger and otherwise healthy population. This review presents some emerging concepts that will likely shape efforts to develop active and passive immunization interventions in response to the reemergence of these bacterial pathogens.
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Vacunas Bacterianas/inmunología , Clostridioides difficile/inmunología , Infecciones por Clostridium/inmunología , Staphylococcus aureus Resistente a Meticilina/inmunología , Infecciones Estafilocócicas/inmunología , Vacunas Estafilocócicas/inmunología , Animales , Antígenos Bacterianos/inmunología , Infecciones por Clostridium/epidemiología , Femenino , Humanos , Inmunidad Celular/inmunología , Masculino , Ratones , Infecciones Estafilocócicas/epidemiología , Células TH1/inmunología , Células Th17/inmunología , Factores de Virulencia/inmunologíaRESUMEN
Shigellosis causes considerable public health burden, leading to excess deaths as well as acute and chronic consequences, particularly among children living in low-income and middle-income countries (LMICs). Several Shigella vaccine candidates are advancing in clinical trials and offer promise. Although multiple target populations might benefit from a Shigella vaccine, the primary strategic goal of WHO is to accelerate the development and accessibility of safe, effective, and affordable Shigella vaccines that reduce mortality and morbidity in children younger than 5 years living in LMICs. WHO consulted with regulators and policy makers at national, regional, and global levels to evaluate pathways that could accelerate regulatory approval in this priority population. Special consideration was given to surrogate efficacy biomarkers, the role of controlled human infection models, and the establishment of correlates of protection. A field efficacy study in children younger than 5 years in LMICs is needed to ensure introduction in this priority population.
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Disentería Bacilar , Vacunas contra la Shigella , Niño , Humanos , Países en Desarrollo , Disentería Bacilar/prevención & control , Disentería Bacilar/epidemiologíaRESUMEN
Acknowledging the fallibilities of recalling events from more than three decades ago, the recollection of Richard Carter's impact on the identification and development of Pfs25, a major surface protein of Plasmodium falciparum zygotes and ookinetes, and target of malaria transmission-blocking vaccines, remains unassailable. In fondest memories of Richard Carter's many contributions, herein retells some memorable events along the tortuous journey toward the development of Pfs25 vaccines.
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Research and innovation have been fundamental to many of the successes in immunization thus far, and will play important roles in the future success of Immunization Agenda 2030 (IA2030). Strategic Priority 7 (SP7) of IA2030, which addresses research and innovation, is explicitly informed by country needs and priorities, and aims to strengthen the innovation ecosystem through capacity building and collaboration at country, regional, and global levels. SP7 identifies four key focus areas: (1) "needs-based innovation", (2) "new and improved products, services, and practices", (3) "evidence for implementation", and (4) "local capacity". Strategic interventions in these key focus areas apply the lessons of the Global Vaccine Action Plan and the "Decade of Vaccines" to emphasize local innovation, promote the use of research by countries to improve program performance and impact, and encourage capacity building for the development and implementation of innovations. The proposed approach will maintain a focus on the development of new vaccines and the improvement of existing vaccines, and increase attention to innovation in service delivery. Monitoring and evaluation will foster evidence-based priority setting at the country level and help to ground the global research and development (R&D) agenda in the needs of communities. Together, these approaches are intended to harness the power of research and innovation more effectively, to meet the challenges of the future and achieve the ambitious goals of IA2030.
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Seven viruses cause at least 15% of the total cancer burden. Viral cancers have been described as the "low-hanging fruit" that can be potentially prevented or treated by new vaccines that would alter the course of global human cancer. Kaposi sarcoma herpesvirus (KSHV or HHV8) is the sole cause of Kaposi sarcoma, which primarily afflicts resource-poor and socially marginalized populations. This review summarizes a recent NIH-sponsored workshop's findings on the epidemiology and biology of KSHV as an overlooked but potentially vaccine-preventable infection. The unique epidemiology of this virus provides opportunities to prevent its cancers if an effective, inexpensive, and well-tolerated vaccine can be developed and delivered.
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World Health Organization (WHO) preferred product characteristics describe preferences for product attributes that would help optimize value and use to address global public health needs, with a particular focus on low- and middle-income countries. Having previously published preferred product characteristics for both maternal and paediatric respiratory syncytial virus (RSV) vaccines, WHO recently published preferred product characteristics for monoclonal antibodies to prevent severe RSV disease in infants. This article summarizes the key attributes from the preferred product characteristics and discusses key considerations for future access and use of preventive RSV monoclonal antibodies.
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Enfermedades Transmisibles , Infecciones por Virus Sincitial Respiratorio , Vacunas contra Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antivirales , Niño , Humanos , Inmunización Pasiva , Lactante , Infecciones por Virus Sincitial Respiratorio/prevención & control , Organización Mundial de la SaludRESUMEN
Invasive group A streptococcal (Strep A) infections occur when Streptococcus pyogenes, also known as beta-hemolytic group A Streptococcus, invades a normally sterile site in the body. This article provides guidelines for establishing surveillance for invasive Strep A infections. The primary objective of invasive Strep A surveillance is to monitor trends in rates of infection and determine the demographic and clinical characteristics of patients with laboratory-confirmed invasive Strep A infection, the age- and sex-specific incidence in the population of a defined geographic area, trends in risk factors, and the mortality rates and rates of nonfatal sequelae caused by invasive Strep A infections. This article includes clinical descriptions followed by case definitions, based on clinical and laboratory evidence, and case classifications (confirmed or probable, if applicable) for invasive Strep A infections and for 3 Strep A syndromes: streptococcal toxic shock syndrome, necrotizing fasciitis, and pregnancy-associated Strep A infection. Considerations of the type of surveillance are also presented, noting that most people who have invasive Strep A infections will present to hospital and that invasive Strep A is a notifiable disease in some countries. Minimal surveillance necessary for invasive Strep A infection is facility-based, passive surveillance. A resource-intensive but more informative approach is active case finding of laboratory-confirmed Strep A invasive infections among a large (eg, state-wide) and well defined population. Participant eligibility, surveillance population, and additional surveillance components such as the use of International Classification of Disease diagnosis codes, follow-up, period of surveillance, seasonality, and sample size are discussed. Finally, the core data elements to be collected on case report forms are presented.