Abstract Objective: To identify and describe learnings from past pandemics and to suggest a framework for vaccine development as part of epi/pandemic readiness. Source of data: Articles/ reviews/letters on pandemic preparedness/ vaccines published between 2005 and 2022 in PubMed, MEDLINE, MedRxiv, BioRxiv, Research Square, Gates Open Research; who. int, cepi.net, visualcapitalist.com, airfinity.com, ted.com websites; press releases. Summary of findings: Disease pandemics caused by emerging pathogens impacted the social development, health and wealth of most societies in human history. In an outbreak, the first months determine its course. To block an exponential spread and the development of an epi/ pandemic early, vaccine availability in sufficient quantities is of paramount importance. It is inevitable that new human viruses will emerge. Any future pandemic will come likely from RNA viruses through zoonotic or vector transmission, but we cannot predict when or where “Disease X” will strike. Public health, scientific and societal readiness plans need to include: continuous identification of new viruses in common mammalian reservoir hosts; continuous epidemiological surveillance, including wastewater sampling; establishment of prototype vaccine libraries against various virus families sharing functional and structural properties; testing of various and innovative vaccine platforms including mRNA, vector, nasal or oral vaccines for suitability by virus family; functional clinical trial sites and laboratory networks in various geographies; more efficient phasing of preclinical and clinical activities; global harmonization and streamlining of regulatory requirements including pre-established protocols; and societal preparedness including combating any pandemic of misinformation. Conclusions: “Outbreaks are unavoidable, pandemics are optional”. Objective epipandemic epi data Articles reviewsletters reviews letters 200 202 PubMed MEDLINE MedRxiv BioRxiv Square who int cepinet cepi net cepi.net visualcapitalistcom visualcapitalist com visualcapitalist.com airfinitycom airfinity airfinity.com tedcom ted websites releases findings history outbreak course early importance emerge transmission X strike include hosts surveillance sampling properties mRNA family geographies activities preestablished pre established protocols misinformation Conclusions Outbreaks unavoidable optional. optional . optional” 20 2

Abstract Objective: Through a literature review, make recommendations regarding immunizations in people living with Inborn Error of Metabolism (IEM) in Brazil, assess the possible impact on metabolic decompensations after immunization, and if this specific population may have an impaired immune response to vaccines. Source of data: The MeSH Terms vaccination OR vaccine OR immunization associated with the term inborn error of metabolism AND recommendation were used in combination with search databases. Only articles published after 1990, in the languages English, Spanish, French or Portuguese, human-related were included. Synthesis of data: A total of 44 articles were included to make the following recommendations. Individuals with IEMs need to be up to date with their immunizations. Regarding which vaccines should be offered, children and adults should follow the routine immunization schedules locally available, including the COVID-19 vaccines. The only exception is the rotavirus vaccine for hereditary fructose intolerance. The benefit of immunization outweighs the very low risk of metabolic decompensation. Since not all patients will have an adequate immune response, measuring antibody conversion and titers is recommended Conclusions: All patients should receive age-appropriate immunizations in their respective schedules without delays. The only situation when vaccination may be contraindicated is with oral rotavirus vaccine in hereditary fructose intolerance. Monitoring the levels of antibodies should be done to detect any immune dysfunction or the necessity for boosters. A personalized immunization schedule is ideal for patients with IEMs. The reference organizations could improve their recommendations to address all IEMs, not only some of them. Objective review IEM (IEM Brazil data databases 1990 English Spanish Portuguese humanrelated human related 4 offered available COVID19 COVID 19 COVID-1 intolerance decompensation Conclusions ageappropriate age appropriate delays boosters them 199 COVID1 1 COVID-

RESUMO A infecção pelo poliovírus causa paralisia em 1 de cada 200 pessoas infectadas. O uso de vacinas seguras e eficazes, tanto vacinas inativadas contra o poliovírus quanto vacinas orais contendo poliovírus atenuado (VOP), significa que restam apenas dois bolsões de poliovírus selvagem tipo 1, um no Afeganistão e outro no Paquistão. No entanto, a VOP pode reverter à virulência, causando surtos de poliovírus circulante derivado de vacina (cPVDV). No período 2020-2022, o cPVDV tipo 2 (cPVDV2) foi responsável por 97% a 99% dos casos de poliomielite, principalmente na África. Entre janeiro e agosto de 2022, o cPVDV2 foi detectado em amostras de esgoto em Israel, no Reino Unido e nos Estados Unidos da América, onde também houve um caso de paralisia flácida aguda causada pelo cPVDV2. A Organização Pan-Americana da Saúde alertou que, devido à queda nas taxas de vacinação (cobertura média de 80% em 2022), o Brasil, o Haiti, o Peru e a República Dominicana correm um risco muito alto de reintrodução do poliovírus e outros oito países da América Latina correm um risco alto. A VOP monovalente Sabin tipo 2 tem sido usada para controlar surtos de PVDV2, mas seu uso também pode levar a surtos. Para resolver esse problema, foi desenvolvida uma nova VOP2 (nVOP2), mais estável geneticamente, para combater o cPVDV2. Em 2020, a nVOP2 entrou na Lista de Uso Emergencial da Organização Mundial da Saúde. A distribuição de uma nova vacina incluída na Lista de Uso Emergencial em contextos de massa para conter surtos requer medidas originais de preparação operacional e regulatória em âmbito local.

RESUMEN La infección por poliovirus ocasiona parálisis en hasta 1 de cada 200 personas infectadas. La utilización de vacunas con poliovirus inactivados y de vacunas antipoliomielíticas orales con poliovirus vivos atenuados (OPV) seguras y eficaces ha logrado que solo queden dos focos de poliovirus salvaje de tipo 1, en Afganistán y Pakistán. Sin embargo, las vacunas con OPV pueden revertir a la virulencia y producir brotes de poliovirus circulantes de origen vacunal (cVDPV). Durante el período 2020-2022, el cVDPV de tipo 2 (cVDPV2) fue la causa del 97-99% de los casos de poliomielitis, sobre todo en África. Entre enero y agosto del 2022, se encontró el cVDPV2 en muestras de aguas residuales en Estados Unidos de América, donde se produjo un caso de parálisis flácida aguda por el cVDPV2, Israel y Reino Unido y. La Organización Panamericana de la Salud ha advertido que, tras la caída de las tasas de vacunación (con una cobertura promedio del 80% en el 2022), Brasil, Haití, Perú y República Dominicana corren un riesgo muy alto de reintroducción del poliovirus, en tanto que otros ocho países de América Latina se encuentran en una situación de alto riesgo. La OPV monovalente de tipo 2 de Sabin se ha utilizado para controlar los brotes de VDPV2, pero su empleo también podría ocasionar brotes. Para hacer frente a este problema, se creó una nueva OPV2 (nOPV2) contra el cVDPV2, genéticamente más estable, que en el 2020 se incluyó en la lista de uso en emergencias de la Organización Mundial de la Salud. El despliegue a gran escala de una nueva vacuna incluida en la lista de uso en emergencias con el fin de contener los brotes exige una extraordinaria preparación regulatoria y operativa local.

ABSTRACT Poliovirus infection causes paralysis in up to 1 in 200 infected persons. The use of safe and effective inactivated poliovirus vaccines and live attenuated oral poliovirus vaccines (OPVs) means that only two pockets of wild-type poliovirus type 1 remain, in Afghanistan and Pakistan. However, OPVs can revert to virulence, causing outbreaks of circulating vaccine-derived poliovirus (cVDPV). During 2020–2022, cVDPV type 2 (cVDPV2) was responsible for 97–99% of poliomyelitis cases, mainly in Africa. Between January and August 2022, cVDPV2 was detected in sewage samples in Israel, the United Kingdom and the United States of America, where a case of acute flaccid paralysis caused by cVDPV2 also occurred. The Pan American Health Organization has warned that Brazil, the Dominican Republic, Haiti and Peru are at very high risk for the reintroduction of poliovirus and an additional eight countries in Latin America are at high risk, following dropping vaccination rates (average 80% coverage in 2022). Sabin type 2 monovalent OPV has been used to control VDPV2 outbreaks, but its use could also lead to outbreaks. To address this issue, a more genetically stable, novel OPV2 (nOPV2) was developed against cVDPV2 and in 2020 was granted World Health Organization Emergency Use Listing. Rolling out a novel vaccine under the Emergency Use Listing in mass settings to contain outbreaks requires unique local regulatory and operational preparedness.

OBJETIVO: Determinar a segurança, imunogenicidade e eficácia de duas doses da vacina contra o rotavírus em lactentes brasileiros saudáveis. MÉTODOS: Foi realizado um estudo randomizado, multicêntrico, duplo-cego e controlado por placebo no Brasil, México e Venezuela. Os lactentes receberam duas doses orais de vacina ou placebo aos 2 e 4 meses de idade, juntamente com as imunizações de rotina, exceto a vacina oral contra poliomielite (VOP). O presente estudo relata apenas os resultados obtidos em Belém, Brasil, onde o número de indivíduos por grupo e os títulos da vacina viral foram os seguintes: 194 (104,7 unidades formadoras de focos - UFF), 196 (10(5,2) UFF), 194 (10(5,8) UFF) e 194 (placebo). A resposta de anticorpos anti-rotavírus (anti-RV) foi avaliada em 307 indivíduos. A gravidade clínica dos episódios de gastroenterite (GE) foi determinada através de um escore com 20 pontos, onde um valor > 11 foi considerado como GE grave. RESULTADOS: As taxas de sintomas gerais solicitados foram semelhantes tanto nos indivíduos que receberam a vacina como naqueles a quem se administrou placebo. Aos 2 meses após a segunda dose, ocorreu resposta em termos de IgA sérica para RV em 54,7 a 74,4% dos vacinados. Não houve interferência na imunogenicidade das vacinas de rotina. A eficácia da vacina contra qualquer gastroenterite por rotavírus (GERV) foi de 63,5% (IC95% 20,8-84,4) para a maior concentração (10(5,8) UFF). A eficácia foi de 81,5% (IC95% 44,5-95,4) contra GERV grave. Em sua maior concentração (10(5,8) UFF), a RIX4414 conferiu uma proteção de 79,8% (IC95% 26,4-96,3) contra GERV grave causada pela amostra G9. CONCLUSÕES: A RIX4414 foi altamente imunogênica com baixa reatogenicidade, e não interferiu na resposta sérica à difteria, tétano, coqueluche, hepatite B e antígenos Hib. Duas doses da RIX4414 conferiram proteção significativa contra a GE grave causada pelo RV.

OBJECTIVE: To determine the safety, immunogenicity and efficacy of two doses of rotavirus vaccine in healthy Brazilian infants. METHODS: A randomized, multicenter, double-blind, placebo-controlled trial was conducted in Brazil, Mexico and Venezuela. Infants received two oral doses of vaccine or placebo at 2 and 4 months of age, concurrently with routine immunizations, except for oral poliomyelitis vaccine (OPV). This paper reports results from Belém, Brazil, where the number of subjects per group and the viral vaccine titers were: 194 (10(4.7) focus forming units - FFU), 196 (10(5.2) FFU), 194 (10(5.8) FFU) and 194 (placebo). Anti-rotavirus (anti-RV) antibody response was assessed in 307 subjects. Clinical severity of gastroenteritis episodes was measured using a 20-point scoring system with a score of > 11 defined as severe GE. RESULTS: The rates of solicited general symptoms were similar in vaccine and placebo recipients. At 2 months after the second dose, a serum IgA response to RV occurred in 54.7 to 74.4% of vaccinees. No interference was seen in the immunogenicity of routine vaccines. Vaccine efficacy against any rotavirus gastroenteritis (RVGE) was 63.5% (95%CI 20.8-84.4) for the highest concentration (10(5.8) FFU). Efficacy was 81.5% (95%CI 44.5-95.4) against severe RVGE. At its highest concentration (10(5.8) FFU), RIX4414 provided 79.8% (95%CI 26.4-96.3) protection against severe RVGE by G9 strain. CONCLUSIONS: RIX4414 was highly immunogenic with a low reactogenicity profile and did not interfere with seroresponse to diptheria, tetanus, pertussis, hepatitis B and Hib antigens. Two doses of RIX4414 provided significant protection against severe GE caused by RV.

Objective. To assess the epidemiology and impact of traveler's diarrhea (TD) among visitors to the city of Fortaleza, Ceará, Brazil, as part of a global study on TD carried out in four countries. Methods. Within a cross-sectional survey, questionnaires were completed by departing travelers at the Fortaleza airport between March 1997 and February 1998. The questions inquired about demographics, duration of stay, reason for their visit, pretravel health advice they had received, risky food and beverage consumption while in Fortaleza, and quality of life during the visit to Fortaleza in relation to having or not having contracted TD. Results. A total of 12 499 questionnaires were analyzed. The most common reason that the visitors gave for their travel to Fortaleza was a holiday (60.3%). The total diarrhea attack rate was 13.4%. Younger people (< 36 years) had significantly higher TD attack rates than did older persons. Using a logistic regression model, we investigated the visitors' risk factors, including age, gender, length of stay, and trip's purpose. According to that analysis, characteristics that are slightly predictive of TD are gender, length of stay, and visiting as a tourist rather than for some other purpose. Characteristics that protect against contracting TD include being older and traveling for business rather than for some other reason. Of those who were incapacitated by TD, the mean duration of the impairment was 42 hours. Conclusions. TD affected the travel plans and activities of many of the visitors to Fortaleza. Further, although aware of the health risks, the majority of those travelers did not avoid all potentially contaminated food or beverage items. Given this pattern of behavior, future efforts to combat TD may have to depend on such other alternative strategies as new vaccines.

Objetivo. Evaluar la epidemiología y el impacto de la diarrea del viajero (DV) en personas que visitan Fortaleza, Brasil, como parte de un estudio general sobre la DV efectuado en cuatro países. Métodos. Se realizó una encuesta transversal en la que se pidió a personas en el aeropuerto que salían de Fortaleza entre marzo de 1997 y febrero de 1998 que completaran un cuestionario. Había preguntas sobre sus características demográficas, la duración de su estancia, la razón de la visita, los consejos que habían recibido antes del viaje, el consumo de alimentos y bebidas peligrosas en Fortaleza, y la calidad de vida durante su visita en relación con la presencia o ausencia de DV. Resultados. Se examinó un total de 12 499 cuestionarios. La razón citada con mayor frecuencia para haber viajado a Fortaleza fue tomarse vacaciones (60,3%). La tasa de ataque global fue de 13,4%. Las personas más jóvenes (< 36 años) tuvieron tasas de ataque mucho más altas que las de edad más avanzada. Usamos un modelo de regresión logística para investigar los factores de riesgo que tenían los turistas, entre ellos la edad, el sexo, la duración de la estancia y el motivo del viaje. Según los resultados de ese análisis, las características que predicen levemente la aparición de DV son el sexo, la duración de la estancia y el estar en viaje de turismo y no de cualquier otro tipo. Ser una persona de mayor edad y haber viajado por razones de negocio en lugar de otros motivos son factores que protegen contra la DV. De las personas que sufrieron discapacitación debido a la DV, la duración media del trastorno fue de 42 horas. Conclusiones. La VD afectó a los planes y actividades de turismo de muchas de las personas que visitaron Fortaleza. Aunque sabían que corrían un riesgo, la mayoría de esos viajeros no se abstuvieron de consumir alimentos o bebidas que podían estar contaminados. En vista de que así se comportan los viajeros, en un futuro cualquier iniciativa orientada a combatir la DV deberá depender de estrategias de otra índole, como por ejemplo, la aplicación de una nueva vacuna.

Objectives: Varicella has more serious consequences in adolescents and adults. Recent reports from Europe and Asia show an increasing number of adolescents and young adults being seronegative. As there is only limited data on varicella zoster virus (VZV) seroprevalence in Brazil and to facilitate the strategy for varicella vaccination we conducted a VZV seroprevalence study in Brazil. Methods: This population-based, cross sectional seroepidemiology study was performed in 4 different regions of Brazil. The studied population was stratified according to gender, age and socioeconomic status. VZV IgG antibodies were analyzed by ELISA. Results: 3,879 subjects aged 1Œ40 years were included into the study. The overall anti-VZV seropositivity rate across all age groups and centers in Brazil was 85.4%. There was a strong age relationship. Especially in the South East and South seroprevalence was low in the age group 1-5 years (44.5% and 57.8%, respectively) while in the North the rate was 88.9%. Overall, Varicella infection was independent of the socioeconomic level, but in the youngest age groups (1-10 years) seroprevalence rates were significantly lower in the high/medium socioeconomic class for most regions. Clinical history of chickenpox correlates well with anti-VZV seropositivity with a predictive value of 95.1% Conclusions: In preadolescence a substantial proportion of the Brazilian population is susceptible to Varicella infection, and a considerable part of the adolescents and young adults remain VZV-seronegative and are thus also at risk

Objetivos: La varicela tiene consecuencias más graves en adolescentes y adultos. Relatos recientes de Europa y Asia muestran un número creciente de adolescentes y adultos jóvenes seronegativos. Como son pocos los datos sobre la prevalencia de antiVZV en Brasil y con el objetivo de definir estrategias para la inmunización contra la varicela, realizamos un estudio de seroprevalencia para el VZV (virus varicela Zoster) en diferentes partes de Brasil. Método: Este estudio seroepidemiológico transversal y poblacional fue realizado en cuatro diferentes regiones de Brasil. La población estudiada fue estratificada por sexo, edad y situación socioeconómica. Fueron analizados por el método Elisa anticuerpos IgG, antiVZV. Resultados: Fueron incluidos en el estudio 3 879 individuos de 1 a 40 años. La tasa de seropositivos de antiVZV en todos los grupos etarios y centros en Brasil fue de 85,4%. Se evidenció una fuerte correlación con la edad. Especialmente en el sureste y sur la seroprevalencia fue menor en el grupo etario de 1-5 años (44,5% y 57,8%, respectivamente. En la región norte esta tasa fue de 88,9%. Conclusiones: En la preadolescencia una proporción substancial de la población brasileña es susceptible a la varicela y una parte considerable de adolescentes y adultos jóvenes se mantienen seronegativos y, consecuentemente, en riesgo

Avaliou-se a prevalência de anticorpos para as hepatites A e B em 3.653 indivíduos, em quatro regiões brasileiras. As prevalências de anti-VHA e de anti-HBc foram 64,7% e 7,9%, respectivamente. Prevalências mais elevadas de anti-VHA (92,8%) e de anti-HBc (21,4%) foram observadas na região Norte. Em outras regiões, prevalências de anti-VHA acima de 90% foram alcançadas apenas em idades mais avançadas, indicando uma endemicidade intermediária e prevalência significativamente mais elevada foi observada no grupo de baixo nível sócio-econômico, entre 1 e 30 anos. Para o anti-HBc observou-se um aumento na prevalência entre adolescentes e uma prevalência significativamente mais elevada no grupo de baixo nível sócio-econômico, entre 1 e 20 anos. Prevalência de 3,1% foi encontrada em crianças de 1 ano, sugerindo a transmissão vertical. Os principais resultados deste estudo, indicam que pré-adolescente/adolescentes de algumas cidades brasileiras estão em risco para as hepatites A e B, mas por diferentes motivos.

The prevalence of antibodies to hepatitis A and B virus was assessed in 3,653 subjects across four regions of Brazil. The anti-HAV and anti-HBc seroprevalence were 64.7% and 7.9%, respectively. The highest anti-HAV (92.8%) and anti-HBc (21.4%) rates were seen in the Northern region. In other regions, anti-HAV seroprevalence over 90% was only reached in the more elderly, indicating an intermediate endemicity and a significantly higher anti-HAV prevalence was seen in the low socioeconomic group between 1-30 years. With respect to anti-HBc seroprevalence an increase was seen in adolescents and there was a significantly higher anti-HBc prevalence in the lower socioeconomic group between 1-20 years. A 3.1% anti-HBc prevalence was seen in one-year-old infants, suggesting a vertical transmission. The major findings of this study indicate that the pre-adolescent and adolescent population in some Brazilian cities are at greatest risk from both hepatitis A and B infection, but for different reasons.