Safety and immunogenicity of different booster vaccination schemes for COVID-19 used in El Salvador.

Purpose: The effectiveness of coronavirus disease 2019 (COVID-19) vaccination schemes and the combination of vaccines of various platforms for administering booster doses is still being studied since it will depend on the population's response to vaccines. We aimed to evaluate the safety, protection, and immunogenicity of the Salvadorean population's third dose booster COVID-19 vaccine and the potential benefit of homologous vs. heterologous regimens. Materials and Methods: This is an analytical observational cohort study in a population aged 18 to 65 years that was primarily vaccinated with AstraZeneca, Sinovac, or Pfizer/BioNTech. Volunteers were recruited (n=223) and followed up for 3 months after receiving the 3rd vaccine (BNT162b2) as a booster. Adverse reactions were monitored, serum anti-spike immunoglobulin G (IgG) was assessed by chemiluminescence, and a polymerase chain reaction was carried out when subjects developed clinical signs. Results: The cohorts finally included 199 participants, and we observed only mild adverse effects in all cohorts. A significant increase in specific IgG levels was found after the booster dose in all cohorts. The heterologous scheme with Sinovac showed the greatest increase in antibody titer, and a decrease was observed in all participants after 3 months. During the follow-up period, 30 participants showed symptomatology compatible with COVID-19, but only four were laboratory-confirmed and they showed mild clinical signs. Conclusion: These findings indicate that the booster doses used were safe and promoted an immediate increase in immunogenicity, which decreased over time. The heterologous regimen showed stronger immunogenicity compared to the messenger RNA-based homologous scheme.

Immunogenicity and tolerability of a bivalent virus-like particle norovirus vaccine candidate in children from 6 months up to 4 years of age: A phase 2 randomized, double-blind trial.

We conducted a dose-finding phase 2 study of the HilleVax bivalent virus-like particle (VLP) vaccine candidate (HIL-214) in two cohorts of children, 6-≤12 months and 1-≤4 years of age (N = 120 per cohort), in Panama and Colombia (ClinicalTrials.gov, identifier NCT02153112). On Day 1, children randomized to one of the four equal groups received intramuscular injections of four different HIL-214 formulations containing 15/15, 15/50, 50/50, or 50/150 µg of GI.1/GII.4c genotype VLPs and 0.5 mg Al(OH)3. On Day 29, half the children in each group received a second vaccination (N = 60), while the other half received saline placebo injections to maintain the blind. VLP-specific ELISA Pan-Ig and histo-blood group binding antigen-blocking antibodies (HBGA) were measured on Days 1, 29, 57 and 210. On Day 29, after one dose, there were large Pan-Ig and HBGA responses in both age cohorts with some indication of dose-dependence, and higher geometric mean titers (GMT) in the older children. A further increase in titers was observed 28 days after a second dose in the 6-≤12-month-old groups, but less so in the 1-≤4-year-old groups; GMTs at Day 57 were broadly similar across doses and in both age groups. GMTs of Pan-Ig and HBGA persisted above baseline up to Day 210. All formulations were well tolerated with mostly mild-to-moderate transient solicited adverse events reported by parents/guardians, and no vaccine-related serious adverse events occurred. Further development of HIL-214 is warranted to protect the most susceptible young children against norovirus.

Safety and immunogenicity of SCB-2019, an adjuvanted, recombinant SARS-CoV-2 trimeric S-protein subunit COVID-19 vaccine in healthy 12-17 year-old adolescents.

We previously demonstrated the efficacy of the COVID-19 vaccine candidate, SCB-2019, in adults in the SPECTRA phase 2/3 efficacy study. We extended the study to include 1278 healthy 12-17-year-old adolescents in Belgium, Colombia, and the Philippines who received either two doses of SCB-2019 or placebo 21 days apart, to assess immunogenicity as neutralizing antibodies against prototype SARS-CoV-2 and variants of concern, and safety and reactogenicity as solicited and unsolicited adverse events with a comparator group of young adults (18-25 years). In participants with no evidence of prior SARS-CoV-2 infection SCB-2019 immunogenicity in adolescents was non-inferior to that in young adults; respective geometric mean neutralizing titers (GMT) against prototype SARS-CoV-2 14 days after the second vaccination were 271 IU/mL (95% CI: 211-348) and 144 IU/mL (116-178). Most adolescents (1077, 84.3%) had serologic evidence of prior SAR-CoV-2 exposure at baseline; in these seropositive adolescents neutralizing GMTs increased from 173 IU/mL (135-122) to 982 IU/mL (881-1094) after the second dose. Neutralizing titers against Delta and Omicron BA SARS-CoV-2 variants were also increased, most notably in those with prior exposure. SCB-2019 vaccine was well tolerated with generally mild or moderate, transient solicited and unsolicited adverse events that were comparable in adolescent vaccine and placebo groups except for injection site pain - reported after 20% of SCB-2019 and 7.3% of placebo injections. SCB-2019 vaccine was highly immunogenic against SARS-CoV-2 prototype and variants in adolescents, especially in those with evidence of prior exposure, with comparable immunogenicity to young adults. Clinical trial registration: EudraCT 2020-004272-17; ClinicalTrials.gov NCT04672395.

Avaliação da expressão de genes relacionados à biossíntese de lipooligossa- carídeo (LOS) na cepa vacinal de Bordetella pertussis do Instituto Butantan

Pertussis is a highly contagious respiratory disease caused by the Gram-negative bacterium Bordetella pertussis, which, although preventable by vaccination, still represents a public health problem today. Among the vaccines available, there are formulations with inactivated whole bacteria (wP) that generate lasting immunity, but may present adverse effects, and acellular formulations (aP), containing purified antigens and associated with milder adverse effects, but less lasting immunity. The adverse effects that may occur in wP were attributed to Lipooligosaccharide (LOS), present in outer membrane of B. pertussis. It is known that the structure of LOS can vary between strains and also that is a variation in the activation of TLR-4, which can lead to differences in the reactogenicity of vaccines. In 2015, the genomic sequencing of the vaccine strain of B. pertussis (Bp137) allowed the characterization of the Brazilian pertussis vaccine strain and the main genes related to the LOS synthesis pathway and some genes related to changes in Lipid A were described. “In silico” mapped genes whose products are linked to modifications in the acylated chains or in the phosphate group of Lipid A, such as pagL and pagP, and the lgm locus, related to the addition of glucosamine to the phosphate groups. These changes can lead to a greater or lesser activation of TLR-4 and production of cytokines, modulating the immune response. In this sense, the objective of this work was to deepen the characterization studies of the LOS of Bp137 to confirm whether the modifications found "in silico" actually occur in some in vivo condition, through the evaluation of the lgmA, pagP, pagL and waaC genes, related to the synthesis and modification of the LOS. The pertussis vaccine production strain Bp137 was cultivated on a laboratory scale, and accompanied by the in-process control steps commonly performed for the production of the pertussis vaccine. The pertussis vaccine production strain Bp137 was cultivated on a laboratory scale, and accompanied by the in-process control steps commonly performed for the production of the pertussis vaccine. From this culture, the extraction of total RNA was carried out, its concentration and purity were determined, for analysis of gene expression by conventional PCR and Real Time PCR. Bacterial growth was evidenced by Opacity and Optical Density; the specificity by purity tests, agglutinogens and Western blot of PT and FHA virulence factors. RNA with reasonable quality was obtained for gene expression analysis experiments and there was no genomic DNA. In the amplification of cDNA of Bp137, the amplification of the lgmA, pagP, pagL and waaC genes was observed, indicating that these genes are possibly expressed in Bp137. The Real Time PCR reactions confirmed the expression of lgmA in the Bp137 strain. As a future perspective, the expression by Real Time PCR for the target genes pagP, pagL and waaC should be confirmed. The results indicate that these genes are possibly ex- pressed in the Bp137 strain, but further studies are needed to obtain such confirmation. The characterization of B. pertussis LOS becomes even more important due to the possibility of using Lipid A as a vaccine adjuvant or even for future interventions to reduce vaccine reactogenicity.

A coqueluche é uma doença respiratória altamente contagiosa causada pela bactéria Gram-negativa Bordetella pertussis, que embora seja prevenível por vacinação, ainda hoje representa um problema de saúde pública. Dentre as vacinas disponíveis, há formulações com bactérias inteiras inativadas (wP) que geram imunidade duradoura, mas podem apresentar efeitos adversos, e formulações acelulares (aP), contendo an-tígenos purificados e associada a efeitos adversos mais leves, mas imunidade menos duradoura. Os efeitos adversos que podem ocorrer nas wP foram atribuídos ao Lipo-oligossacarídeo (LOS), presente na membrana externa de B. pertussis. Sabe-se que a estrutura do LOS pode variar entre cepas e também que há uma variação da ativa-ção de TLR-4, o que pode levar a diferenças na reatogenicidade das vacinas. Em 2015 o sequenciamento genômico da cepa vacinal de B. pertussis (Bp137) permitiu a caracterização da cepa produtora da vacina pertussis Brasileira e foram descritos os principais genes relacionados a via de síntese do LOS e alguns genes relacionados a modificações no Lipídio A. As análises “in silico” mapearam genes cujos produtos es-tão ligados a modificações nas cadeias aciladas ou ainda no grupo fosfato do Lipídio A, tais como pagL e pagP, e o locus lgm, relacionado a adição de glucosamina nos grupos fosfatos. Essas alterações podem levar a uma maior ou menor ativação de TLR-4 e produção de citocinas, modulando a resposta imune. Nesse sentido, objeti-vou-se com este trabalho aprofundar os estudos de caracterização do LOS da Bp137 para confirmar se as modificações encontradas “in silico” ocorrem de fato em alguma condição in vivo, através da avaliação dos genes lgmA, pagP, pagL e waaC, relacio-nados à síntese e modificação do LOS. A cepa de produção da vacina pertussis Bp137 foi cultivada em escala laboratorial, acompanhada das etapas de controle em processo comumente realizadas para a produção da vacina pertussis. A partir deste cultivo realizou-se a extração de RNA total, determinou-se sua concentração e pureza, para análise de expressão gênica por PCR convencional e PCR Em Tempo Real. O crescimento bacteriano foi evidenciado por meio da Opacidade e Densidade óptica; a especificidade pelos testes de pureza, aglutinógenos e Western Blot dos fatores de virulência PT e FHA. Obteve-se RNA com qualidade razoável para experimentos de análise de expressão gênica e verificou-se ausência de DNA genômico. Na amplificação de cDNA de Bp137, foi observada a amplificação dos genes lgmA, pagP, pagL e waaC, indicando que possivelmente estes genes estejam expressos na Bp137. As reações de PCR em Tempo Real confirmaram a expressão do lgmA na cepa Bp137. Como perspectiva futura deverá ser confirmada a expressão por PCR em Tempo Real para os genes alvo pagP, pagL e waaC. Os resultados indicam que possivelmente estes genes estejam expressos na cepa de Bp137, porém são necessários mais estudos para obter tal confirmação. A caracterização das LOS de B. pertussis se torna ainda mais importante ainda pela possibilidade do uso do Lipídio A como adjuvante vacinal ou ainda de futuras intervenções para redução da reatogenicidade vacinal.

Neutralizing Antibodies against SARS-CoV-2, Anti-Ad5 Antibodies, and Reactogenicity in Response to Ad5-nCoV (CanSino Biologics) Vaccine in Individuals with and without Prior SARS-CoV-2.

This is the first study outside of clinical trials (phase I-III) evaluating the ability of the Ad5-nCoV vaccine to generate neutralizing antibodies and the factors associated with optimal or suboptimal response. In a longitudinal assay, 346 people (117 with prior COVID-19 and 229 without prior COVID-19) vaccinated with Ad5-nCoV were recruited. The percentage of neutralizing antibodies against SARS-CoV-2 (Surrogate Virus Neutralization Test) and antibodies against Ad5 (ADV-Ad5 IgG ELISA) were quantified pre and post-vaccination effects. The Ad5-nCoV vaccine induces higher neutralizing antibodies percentage in individuals with prior COVID-19 than those without prior COVID-19 (median [IQR]: 98% [97-98.1] vs. 72% [54-90], respectively; p < 0.0001). Furthermore, a natural infection (before vaccination) induces more neutralizing antibodies percentage than immunized individuals without prior COVID-19 (p < 0.01). No patient had vaccine-severe adverse effects. The age, antidepressant, and immunosuppressive treatments, reactogenicity, and history of COVID-19 are associated with impaired antibody production. The anti-Ad5 antibodies increased after 21 days of post-vaccination in all groups (p < 0.01). We recommend the application of a booster dose of Ad5-nCoV, especially for those individuals without previous COVID-19 infection. Finally, the induction of anti-Ad5 antibodies after vaccination should be considered if a booster with the same vaccine is planned.

Methods for predicting vaccine immunogenicity and reactogenicity.

Subjects receiving the same vaccine often show different levels of immune responses and some may even present adverse side effects to the vaccine. Systems vaccinology can combine omics data and machine learning techniques to obtain highly predictive signatures of vaccine immunogenicity and reactogenicity. Currently, several machine learning methods are already available to researchers with no background in bioinformatics. Here we described the four main steps to discover markers of vaccine immunogenicity and reactogenicity: (1) Preparing the data; (2) Selecting the vaccinees and relevant genes; (3) Choosing the algorithm; (4) Blind testing your model. With the increasing number of Systems Vaccinology datasets being generated, we expect that the accuracy and robustness of signatures of vaccine reactogenicity and immunogenicity will significantly improve.

Reactogenicity of Bordetella pertussis vaccines formulations using aluminum adjuvants in Sprague Dawley rats / Reactogenicidad de formulaciones de vacunas de Bordetella pertussis utilizando adyuvantes de aluminio en ratas Sprague Dawley

Combined vaccines for childhood are a strategy in the prevention of several diseases. These can maximize protection and decrease immunization schedules in children. New candidates are getting closer to being able to meet these needs, but they raise numerous strategic questions related to formulation and regulatory aspects. In addition to being immunogenic and protective must have low reactogenicity when combined with other antigens. Adjuvants are important components in achieving these combinations. Therefore, a reactogenicity study was designed for two Bordetella pertussis formulations containing hydroxide or aluminum phosphate in Sprague Dawley rats. Both formulations dose were administered in 0.2 mL intramuscularly. Clinical evaluations, body weight, water consumption, food, temperature, muscle volume, dermal irritability and pathological studies with special interest at the inoculation site were carried out. Only differences in body temperature and muscle volume were found with a slight increase in values with return to normal. The macroscopic study showed lesions at the site of inoculation, consid­ered characteristics of aluminum adjuvants, such as granulomatous abscesses and the increase in regional lymph nodes near the inoculation site. As conclusion, there are no differences between the formulations of B. pertussis with hydroxide or aluminum phosphate resulted in low reactogenicity.

Las vacunas combinadas resultan una estrategia importante en la obtención de vacunas múltiples para la infancia y el uso de adyuvantes es un componente de gran valor en lograr estas combinaciones, además de ser inmunogénicas y protectoras deben tener baja reactogenicidad, cuando se combinan con diferentes antígenos. Por esta razón, se diseñó un estudio de reactogenicidad a dos formulaciones que contenían hidróxido y fosfato de aluminio con antígenos de Bordetella pertussis en ratas Sprague Dawley. Se administró a cada grupo de ensayo una dosis correspondiente de ambas formulaciones en 0,2 mL por vía intramuscular. Se realizaron observaciones clínicas, comportamiento del peso corporal, consumo de agua, alimentos, temperatura corporal, volumen muscular, irritabilidad dérmica y estudios anatomopatológicos macroscópicos, con especial interés en el sitio de inoculación. No se observaron síntomas, ni muertes en los animales durante el estudio. Tampoco se encontraron diferencias entre los grupos experimentales en cuanto al peso corporal, el consumo de agua y de alimentos; los estudios de temperatura corporal y volumetría muscular evidenciaron un ligero incremento en los valores, los cuales involucionaron rápidamente a la normalidad. En el estudio anatomopatológico macroscópico se observaron lesiones a nivel del punto de inoculación, consideradas propias de los adyuvantes que contienen aluminio, tales como formaciones abscedadas de tipo granulomatosas y el aumento de los ganglios linfáticos regionales cercanos al punto de inoculación. Se concluye que las formulaciones en hidróxido y fosfato de aluminio con antígenos de B.pertussis resultaron ser de baja reactogenicidad.

Erradicación de fiebre tifoidea en Holguín. Logro de la Medicina cubana 1972-2016 / Elimination of Typhoid Fever in Holguín. An achievement of cuban Medicine. 1972-2016

Introducción: la fiebre tifoidea es una infección sistémica causada por Salmonella tiphy, a través de la ingesta de alimentos contaminados (fecal-oral). Es un problema de salud pública, especialmente en países en vías de desarrollo. Objetivo: caracterizar la fiebre tifoidea en la provincia de Holguín durante los años 1972-2016. Método: se realizó un estudio descriptivo longitudinal de series de casos reportados de fiebre tifoidea por tarjeta EDO (Enfermedades de Declaración Obligatoria) en la provincia de Holguín desde el año 1972-2016. El universo estuvo constituido por 471 pacientes reportados por fiebre tifoidea, según tarjeta de EDO. Resultados: no se reportaron fallecidos desde el año 1974 y los menores de 15 años fueron los más afectados. El municipio que se mantuvo como de alto riesgo fue Holguín. La aplicación de la vacuna cubana de polisacárido Vi, mucho menos reactogénica y más efectiva que la utilizada anteriormente de calor-fenol, puede ser la causa o parte de la causa para la no ocurrencia de casos en los últimos 10 años en la provincia. Conclusiones: la morbilidad por fiebre tifoidea ha disminuido al igual que el número de brotes y afectados en brotes. Las medidas de control inmediatas y la existencia de un programa de control, además de la nueva vacuna de producción nacional, fabricada por los laboratorios Finlay, han hecho posible tales logros.

Introduction: typhoid fever is a systemic infection caused by Salmonella tiphy through ingestion of contaminated food (fecal-oral). It is a public health problem, especially in developing country. Objective: to characterize typhoid fever in Holguin province during the years 1972-2016. Method: a longitudinal descriptive study of series of reported cases of typhoid by EDO card (Notifiable Diseases) in Holguin province since 1972 to 2016, in order to characterize the typhoid in Holguin province was conducted. The universe consisted of 471 patients reported for typhoid Fever, according to EDO card. Results: no deaths were reported since 1974, children under 15 were the most affected, the Holguin municipality remained as high risk. The application of the Vi much less reactogenic and more effective polysaccharide Cuban vaccine used previously heat-phenol, may be the cause or part of the cause for the non-occurrence of cases in the last 10 years in the province. Conclusions: the morbidity due to typhoid fever has decreased as well as the number of outbreaks and affected in outbreaks. The immediate control measures and the existence of a control program, in addition to the new vaccine of national production, manufactured by the Finlay laboratories, have made such achievements possible.

Safety of the novel influenza viral vector Brucella abortus vaccine in pregnant heifers / Segurança de uma nova vacina vetorial empregando o vírus influenza para Brucella abortus em novilhas prenhes

ABSTRACT: The present study provides the first information about the safety of a new influenza viral vector vaccine expressing the Brucella ribosomal protein L7/L12 or Omp16 containing the adjuvant Montanide Gel01 in pregnant heifers. Immunization of pregnant heifers was conducted via the conjunctival (n=10) or subcutaneous (n=10) route using cross prime and booster vaccination schedules at an interval of 28 days. The vector vaccine was evaluated in comparison with positive control groups vaccinated with B. abortus S19 (n=10) or B. abortus RB51 (n=10) and a negative (PBS+Montanide Gel01; n=10) control group. Clinical studies, thermometry, assessment of local reactogenicity and observation of abortion showed that the vector vaccine via the conjunctival or subcutaneous route was completely safe for pregnant heifers compared to the commercial vaccines B. abortus S19 or B. abortus RB51. The only single adverse event was the formation of infiltration at the site of subcutaneous injection; this reaction was not observed for the conjunctival route.

RESUMO: O presente estudo fornece as primeiras informações sobre a segurança de uma nova vacina usando o vetor viral influenza para expressar as proteínas de Brucella L7/L12 ou Omp16, contendo o adjuvante Montanide Gel01 em novilhas prenhes. A imunização de novilhas prenhes foi realizada através das vias conjuntiva (n=10) ou subcutânea (n=10), empregadas na primovacinação e na dose de reforço. O intervalo foi de 28 dias. A vacina empregando o vetor foi comparada com os grupos de controle positivo, vacinados com B. abortus B19 (n=10) ou B. abortus RB51 (n=10) e um grupo de controle negativo (PBS + Montanide Gel01; n=10). Os estudos clínicos, termometria, reação local e observação do aborto mostraram que a vacina empregando o vetor, aplicada pela via conjuntival ou subcutânea, foi completamente segura para novilhas prenhes, em comparação com as vacinas comerciais B. abortus B19 ou B. abortus RB51. O único efeito adverso foi a formação de infiltrado no local da administração subcutânea; essa reação não foi observada no grupo vacinado pela via conjuntival.

Safety of the novel influenza viral vector Brucella abortus vaccine in pregnant heifers

ABSTRACT: The present study provides the first information about the safety of a new influenza viral vector vaccine expressing the Brucella ribosomal protein L7/L12 or Omp16 containing the adjuvant Montanide Gel01 in pregnant heifers. Immunization of pregnant heifers was conducted via the conjunctival (n=10) or subcutaneous (n=10) route using cross prime and booster vaccination schedules at an interval of 28 days. The vector vaccine was evaluated in comparison with positive control groups vaccinated with B. abortus S19 (n=10) or B. abortus RB51 (n=10) and a negative (PBS+Montanide Gel01; n=10) control group. Clinical studies, thermometry, assessment of local reactogenicity and observation of abortion showed that the vector vaccine via the conjunctival or subcutaneous route was completely safe for pregnant heifers compared to the commercial vaccines B. abortus S19 or B. abortus RB51. The only single adverse event was the formation of infiltration at the site of subcutaneous injection; this reaction was not observed for the conjunctival route.

RESUMO: O presente estudo fornece as primeiras informações sobre a segurança de uma nova vacina usando o vetor viral influenza para expressar as proteínas de Brucella L7/L12 ou Omp16, contendo o adjuvante Montanide Gel01 em novilhas prenhes. A imunização de novilhas prenhes foi realizada através das vias conjuntiva (n=10) ou subcutânea (n=10), empregadas na primovacinação e na dose de reforço. O intervalo foi de 28 dias. A vacina empregando o vetor foi comparada com os grupos de controle positivo, vacinados com B. abortus B19 (n=10) ou B. abortus RB51 (n=10) e um grupo de controle negativo (PBS + Montanide Gel01; n=10). Os estudos clínicos, termometria, reação local e observação do aborto mostraram que a vacina empregando o vetor, aplicada pela via conjuntival ou subcutânea, foi completamente segura para novilhas prenhes, em comparação com as vacinas comerciais B. abortus B19 ou B. abortus RB51. O único efeito adverso foi a formação de infiltrado no local da administração subcutânea; essa reação não foi observada no grupo vacinado pela via conjuntival.

Safety of the novel influenza viral vector Brucella abortus vaccine in pregnant heifers

ABSTRACT: The present study provides the first information about the safety of a new influenza viral vector vaccine expressing the Brucella ribosomal protein L7/L12 or Omp16 containing the adjuvant Montanide Gel01 in pregnant heifers. Immunization of pregnant heifers was conducted via the conjunctival (n=10) or subcutaneous (n=10) route using cross prime and booster vaccination schedules at an interval of 28 days. The vector vaccine was evaluated in comparison with positive control groups vaccinated with B. abortus S19 (n=10) or B. abortus RB51 (n=10) and a negative (PBS+Montanide Gel01; n=10) control group. Clinical studies, thermometry, assessment of local reactogenicity and observation of abortion showed that the vector vaccine via the conjunctival or subcutaneous route was completely safe for pregnant heifers compared to the commercial vaccines B. abortus S19 or B. abortus RB51. The only single adverse event was the formation of infiltration at the site of subcutaneous injection; this reaction was not observed for the conjunctival route.

RESUMO: O presente estudo fornece as primeiras informações sobre a segurança de uma nova vacina usando o vetor viral influenza para expressar as proteínas de Brucella L7/L12 ou Omp16, contendo o adjuvante Montanide Gel01 em novilhas prenhes. A imunização de novilhas prenhes foi realizada através das vias conjuntiva (n=10) ou subcutânea (n=10), empregadas na primovacinação e na dose de reforço. O intervalo foi de 28 dias. A vacina empregando o vetor foi comparada com os grupos de controle positivo, vacinados com B. abortus B19 (n=10) ou B. abortus RB51 (n=10) e um grupo de controle negativo (PBS + Montanide Gel01; n=10). Os estudos clínicos, termometria, reação local e observação do aborto mostraram que a vacina empregando o vetor, aplicada pela via conjuntival ou subcutânea, foi completamente segura para novilhas prenhes, em comparação com as vacinas comerciais B. abortus B19 ou B. abortus RB51. O único efeito adverso foi a formação de infiltrado no local da administração subcutânea; essa reação não foi observada no grupo vacinado pela via conjuntival.

Safety of the novel influenza viral vector Brucella abortus vaccine in pregnant heifers / Segurança de uma nova vacina vetorial empregando o vírus influenza para Brucella abortus em novilhas prenhes

The present study provides the first information about the safety of a new influenza viral vector vaccine expressing the Brucella ribosomal protein L7/L12 or Omp16 containing the adjuvant Montanide Gel01 in pregnant heifers. Immunization of pregnant heifers was conducted via the conjunctival (n=10) or subcutaneous (n=10) route using cross prime and booster vaccination schedules at an interval of 28 days. The vector vaccine was evaluated in comparison with positive control groups vaccinated with B. abortus S19 (n=10) or B. abortus RB51 (n=10) and a negative (PBS+Montanide Gel01; n=10) control group. Clinical studies, thermometry, assessment of local reactogenicity and observation of abortion showed that the vector vaccine via the conjunctival or subcutaneous route was completely safe for pregnant heifers compared to the commercial vaccines B. abortus S19 or B. abortus RB51. The only single adverse event was the formation of infiltration at the site of subcutaneous injection; this reaction was not observed for the conjunctival route.(AU)

O presente estudo fornece as primeiras informações sobre a segurança de uma nova vacina usando o vetor viral influenza para expressar as proteínas de Brucella L7/L12 ou Omp16, contendo o adjuvante Montanide Gel01 em novilhas prenhes. A imunização de novilhas prenhes foi realizada através das vias conjuntiva (n=10) ou subcutânea (n=10), empregadas na primovacinação e na dose de reforço. O intervalo foi de 28 dias. A vacina empregando o vetor foi comparada com os grupos de controle positivo, vacinados com B. abortus B19 (n=10) ou B. abortus RB51 (n=10) e um grupo de controle negativo (PBS + Montanide Gel01; n=10). Os estudos clínicos, termometria, reação local e observação do aborto mostraram que a vacina empregando o vetor, aplicada pela via conjuntival ou subcutânea, foi completamente segura para novilhas prenhes, em comparação com as vacinas comerciais B. abortus B19 ou B. abortus RB51. O único efeito adverso foi a formação de infiltrado no local da administração subcutânea; essa reação não foi observada no grupo vacinado pela via conjuntival.(AU)

Comparison of two commercial vaccines against visceral leishmaniasis in dogs from endemic areas: IgG, and subclasses, parasitism, and parasite transmission by xenodiagnosis.

BACKGROUND: The incidence of zoonotic canine visceral leishmaniasis (CVL) would decrease if dogs were effectively vaccinated; however, additional data on the efficacy of canine vaccines are required for their approved preventative use. PURPOSE: To prospectively evaluate vaccination outcomes using two products commercially available in Brazil, with respect to adverse reactions (reactogenicity), humoral response, disease signs, parasitism, and parasite infectiousness in naturally exposed pet dogs in an endemic area of visceral leishmaniasis (VL). METHODS: From 2010 to 2012, healthy dogs were vaccinated with Leishmune(®) (50 animals) or Leish-Tec(®) (50 animals). Each dog was examined to identify clinical signs during peri- and post-vaccination procedures every 2 months for 11 months to identify the presence of parasites or parasite DNA in splenic samples using culturing or PCR, respectively. Levels of anti-Leishmania IgG, IgG1, and IgG2 were quantified in sera by ELISA and infectiousness was assessed by xenodiagnosis. RESULTS: Adverse effects occurred in 2.2% (1/45) and 13.0% (6/46) of the animals in the Leishmune(®) and Leish-Tec(®) groups, respectively. IgG levels peaked on the 21st day following the first dose of Leishmune(®) and on the 21st day after the second dose of Leish-Tec(®). The final seropositivity rate for IgG was 32.5% (13/40) and 30.9% (13/42) in the Leishmune(®) and Leish-Tec(®) groups, respectively. The Leishmune(®) group presented higher levels of IgG1 and IgG2 compared to the Leish-Tec(®) group (p<0.001), and ELISA reactivity in both vaccinated groups was significantly lower (p<0.001) than in infected positive control dogs. Parasitism was observed in 12.2% (5/41) of the Leishmune(®) group, and 7.9% (3/38) of the Leish-Tec(®) group, with xenodiagnostic transmission rates of Leishmania to Lutzomyia longipalpis of 5.1% (2/39), and 5.4% (2/37), respectively. CONCLUSIONS: No significant differences were observed in dogs vaccinated with Leishmune(®) or Leish-Tec(®), with respect to LVC clinical aspects, parasitism, IgG seropositivity, or dog infectiousness. The Leishmune(®)-vaccinated animals presented higher levels of IgG, IgG1, and IgG2. The animals vaccinated with Leish-Tec(®) exhibited adverse reactions with greater frequency and severity.

17DD yellow fever vaccine: a double blind, randomized clinical trial of immunogenicity and safety on a dose-response study.

OBJECTIVE: To verify if the Bio-Manguinhos 17DD yellow fever vaccine (17DD-YFV) used in lower doses is as immunogenic and safe as the current formulation. RESULTS: Doses from 27,476 IU to 587 IU induced similar seroconversion rates and neutralizing antibodies geometric mean titers (GMTs). Immunity of those who seroconverted to YF was maintained for 10 mo. Reactogenicity was low for all groups. METHODS: Young and healthy adult males (n = 900) were recruited and randomized into 6 groups, to receive de-escalating doses of 17DD-YFV, from 27,476 IU to 31 IU. Blood samples were collected before vaccination (for neutralization tests to yellow fever, serology for dengue and clinical chemistry), 3 to 7 d after vaccination (for viremia and clinical chemistry) and 30 d after vaccination (for new yellow fever serology and clinical chemistry). Adverse events diaries were filled out by volunteers during 10 d after vaccination. Volunteers were retested for yellow fever and dengue antibodies 10 mo later. Seropositivity for dengue was found in 87.6% of volunteers before vaccination, but this had no significant influence on conclusions. CONCLUSION: In young healthy adults Bio-Manguinhos/Fiocruz yellow fever vaccine can be used in much lower doses than usual. INTERNATIONAL REGISTER: ISRCTN 38082350.

An improved whole cell pertussis vaccine with reduced content of endotoxin.

An improved whole cell pertussis vaccine, designated as Plow, which is low in endotoxicity due to a chemical extraction of lipo-oligosaccharide (LOS) from the outer membrane, was evaluated for safety, immunogenicity and potency, comparatively to a traditional whole cell pertussis vaccine. Current whole cell pertussis vaccines are effective but contain large quantities of endotoxin and consequently display local and systemic adverse reactions after administration. Endotoxin is highly inflammatory and contributes considerably to the reactogenicity as well as the potency of these vaccines. In contrast, acellular pertussis vaccines hardly contain endotoxin and are significantly less reactogenic, but their elevated costs limit their global use, especially in developing countries. In this paper, bulk products of Plow and a traditional whole cell vaccine, formulated as plain monocomponents or combined with diphtheria and tetanus toxoids (DTPlow or DTP, respectively) were compared by in vitro and in vivo assays. Chemical extraction of LOS resulted in a significant decrease in endotoxin content (20%) and a striking decline in endotoxin related toxicity (up to 97%), depending on the used in vitro or in vivo test. The LOS extraction did not affect the integrity of the product and, more importantly, did not affect the potency and/or stability of DTPlow. Moreover, hardly any differences in antibody and T-cell responses were observed. The development of Plow is a significant improvement regarding the endotoxicity of whole cell pertussis vaccines and therefore a promising and affordable alternative to currently available whole cell or acellular pertussis vaccines for developing countries.

Reactogenicidad asociada a la administración intradérmica de la vacuna de polio inactivada con un inyector sin aguja / Reactogenicity associated to the intradermally administered inactivated poliovirus vaccine with a needle-free injector

INTRODUCCIÓN: en la medida en que la meta de la erradicación de la poliomielitis llega a su concreción, la necesidad de contar con una vacuna de polio inactivada asequible y apropiada para el uso en países en vías de desarrollo se ha convertido en una meta para la Organización Mundial de la Salud. OBJETIVO: la evaluación de la reactogenicidad de la vacuna de polio inactivada. MÉTODOS: se realizó un estudio multicéntrico con diseño experimental, correspondiente a Fase I-II de un ensayo clínico controlado, aleatorio y a simple ciegas, en 471 lactantes sanos de ambos sexos nacidos entre los meses de julio y agosto de 2006 en Camagüey, cuyos padres brindaron su consentimiento por escrito y que cumplieron con los criterios de inclusión establecidos. Los niños recibieron a las 6, 10 y 14 semanas del nacimiento, tres dosis de vacuna de polio inactivada del Instituto de Sueros de Dinamarca, autorizada para su uso en esta investigación por las autoridades regulatorias nacionales. Al grupo de estudio A, se le administró por la vía intradérmica la dosis reducida de 0,1 mL de vacuna de polio inactivada en la cara anterolateral del muslo izquierdo utilizando el inyector sin aguja Biojector® 2000. El grupo control B recibió la dosis usual de 0,5 mL por la vía intramuscular profunda, administrada en el mismo sitio descrito antes con una jeringuilla prellenada. Se observaron los eventos adversos durante la primera hora, 24, 48, y 72 h subsiguientes, así como a los 7 y 30 d de administrada la vacuna. La reactogenicidad se evaluó inicialmente por el pediatra del área y luego por el médico de familia mediante la observación de los eventos adversos. RESULTADOS: 79,6 por ciento del total de niños asignados al grupo A y 75 por ciento del grupo B finalizaron el protocolo de investigación. No se detectaron eventos adversos moderados o serios. Predominaron las reacciones adversas locales menores, sobre todo induración, dolor y enrojecimiento en el sitio de la inyección. CONCLUSIÓN: el ensayo demostró la seguridad de la vacuna de polio inactivada para su uso por vía intramuscular y reconoció la seguridad del uso de la vía intradérmica y del inyector sin agujas.

INTRODUCTION: as the goal of poliomyelitis eradication is about to be accomplished, the need for an affordable and appropriate inactivated poliovirus vaccine (IPV) for use in developing countries has become a target for WHO. OBJECTIVE: to evaluate the reactogenicity of the inactivated poliovirus vaccine. METHOD: an experimental-type multicenter study was conducted, as part of a Phase I-II controlled clinical randomized and blinded assay, in 471 healthy infants of both sexes born in July and August 2006 in Camagüey province. The parents of the children who met the inclusion criteria gave their consent in writing. The children received three doses of the inactivated poliovirus vaccine at 6, 10 and 14 weeks after birth. This vaccine came form the Institute of Sera in Denmark and had been approved for use in this assay by the Cuban regularoty authorities, Low 0.1 ml inactivated poliovirus vaccine dose was intradermally administered to the study group A in the anterolateral side of the left thigh using the needle-free injector called Biojector ® 2000. The usual 0.5 mL dose was intramuscularly administered on the same site using a pre-filled syringe. The adverse events were observed during the first hour, 24, 48, and 72 hours after the immunization, as well as 7 and 30 days afterwards. The pediatrician in charge of the health area evaluated the reactogenicity at first and then the family physician was in charge of observing the adverse events in the remaining period. RESULTS: the 79.6 percent of children in group A and 75 percent in group B completed the research protocol. Mild local adverse reactions prevailed, mainly induration, pain and redness at the injection site. CONCLUSION: the clinical trial proved the safety of the inactivated poliovirus vaccine for intramuscular administration, and also showed the safety of the intradermal route of administration and of the needle-free injector.

La reactogenicidad y los aspectos inmune específicos de la vacuna pentavalente combinada: DTPw-HepB-Hib en el lactante menor de un año en el Hospital Distrital de Lambaré, Paraguay en 2007-2008 / The reactogenicity and specific immune aspects of the combined pentavalent vaccine: DTPw-HepB-Hib in breastfed babies under one year of age that attended the District Hospital of Lambaré, Paraguay in 2007 and 2008

La vacunación rutinaria de difteria, pertussis y tétanos a células enteras (DPTw) está presente desde 1940 y con elevadas coberturas en muchos países del mundo. La Organización Mundial de la Salud ha aprobado el uso universal de la vacuna anti-hepatitis B (HB) y combinaciones con DPT, en los últimos años ha sido incorporada la vacuna anti-Haemophilus influenzae tipo b (Hib) en programas de vacunación del niño. Es aplicada en Paraguay desde el 2002 a través del Programa Ampliado de Inmunizaciones del Ministerio de Salud Pública y Bienestar Social. Determinamos la reactoinmunogenicidad secundaria a la vacunación primaria pentavalente combinada en infantes concurrentes al Hospital Distrital de Lambaré­Paraguay en los años 2007-2008. Estudio longitudinal, observacional prospectivo de los efectos secundarios y los aspectos inmune- específicos de la vacuna Berna DTPw-HepB-Hib (QUINVAXEMTM) en lactantes menores de un año, a los 2 meses de edad, datos basales y post vacunales (1 mes luego de 3ª dosis). Efectos locales: 30(75%); rubor 17 (42.5%); tumefacción (menos 20 mm); 13 (32.5%); calor local 11 (27.5%). Efectos generales: fiebre: 37 (92.5%) llanto fuerte y persistente: 32(80%); irritabilidad: 23 (57.5%); hiporreactividad 16 (40%), anorexia 8 (20%); Inmunogenicidad: antes de la 1ª dosis; antitetánica IgG (+) 38/40 (95%), anti-difteria (+) IgG 29/40 (72.5%); anti-HBsAg 0/40 (0%) negativos. Respuesta post-vacuna penta comb. (7m. edad): antitetánica IgG 14/14 (100%) (+); anti-difteria IgG 12/14 (83%) (+); anti-HBsAg 14/14 (100%) positivos. Se evidencia la reactogenicidad de grado variable y decreciente. Niveles de anticuerpos de los componentes DT, satisfactorios y la Hep B excelentes

The combined cellular pentavalent vaccine is one the greatest achievements of human kind in the 20th century and is still successful in the 21st century. It is made up of five components and protects against the following diseases: diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae type b. The vaccine provides specific active immunization against infections caused by Corynebacterium diphtheriae, Clostridium tetani, Bordetella pertussis, Haemophilus influenzae type B and the Hepatitis B virus in children from six weeks of age. In Paraguay, it has been used since 2002 through the Widened Program of Immunization (PAI in Spanish) of the Ministry of Public Health. The objective of this work was to determine the secondary reactoinmunogenicity to the primary combined pentavalent vaccination in children attending the District Hospital of Lambaré, Paraguay in 2007 and 2008. This is a longitudinal, prospective observational study to evaluate the secondary effects and immune-specific aspects of the Berna DTPw-HepB-Hib combined pentavalent vaccine (QUINVAXEMTM) applied to breastfed babies under one year old, of both sexes, all races, origins and nutrition statuses in the Hospital of Lambaré. The vaccination was free, according to PAI's guidelines and by consecutive sampling previous written consent of the parents, at 2 months of age. Data were collected at baseline an post-vaccination after one month and a third dose. In a total population of 40 breastfed babies, good nutrition was found in 36 (90%). Local effects were seen in 30 (75%) distributed as follows: blush in 17 (42.5%), tumefaction (less than 20 mm) in 13 (32.5%) and local heat in 11 (27.5%). General effects were distributed as follows: fever in 37 (92.5%), loud and persistent cry in 32 (80%), irritability in 23 (57.5%), hyporeactivity in 16 (40%), anorexia in 8 (20%), hypotonicity and allergy, 2 each (5%), convulsions and paralysis in none. The effects are an average after the three doses with a decreasing trend at the end. The immunogenicity basal data before the 1st dose were as follows: antitetanic IgG (+) 38/40 (95%), antidiphtheria IgG (+) 29/40 (72.5%) and anti HBs Ag (-) 0/40 (0%). Post - vaccination responses (at 7 months old) were as follows: antitetanic IgG (+) 14/14 (100%), antidiphtheria IgG (+) 12/14 (83%) and anti HBs Ag (+) 14/14 (100%). These results show a reactogenicity of variable and decreasing degree. The antibodies levels of the DT components were satisfactory and those of Hep B excellent

La reactogenicidad y los aspectos inmune específicos de la vacuna pentavalente combinada: DTPw-HepB-Hib en el lactante menor de un año en el Hospital Distrital de Lambaré, Paraguay en 2007-2008 / The reactogenicity and specific immune aspects of the combined pentavalent vaccine: DTPw-HepB-Hib in breastfed babies under one year of age that attended the District Hospital of Lambaré, Paraguay in 2007-2008

La vacunación rutinaria de difteria, pertussis y tétanos a células enteras (DPTw) está presente desde 1940 y con elevadas coberturas en muchos países del mundo. La Organización Mundial de la Salud ha aprobado el uso universal de la vacuna anti-hepatitis B (HB) y combinaciones con DPT, en los últimos años ha sido incorporada la vacuna anti-Haemophilus influenzae tipo b (Hib) en programas de vacunación del niño. Es aplicada en Paraguay desde el 2002 a través del Programa Ampliado de Inmunizaciones del Ministeriode Salud Pública y Bienestar Social. Determinamos la reactoinmunogenicidad secundaria a la vacunación primaria pentavalente combinada en infantes concurrentes al Hospital Distrital de Lambaré–Paraguay en los años 2007-2008. Estudio longitudinal,observacional prospectivo de los efectos secundarios y los aspectos inmune- específicos de la vacuna Berna DTPw-HepB-Hib (QUINVAXEMTM) en lactantes menores de un año, a los 2 meses de edad, datos basales y post vacunales (1 mes luego de 3ª dosis). Efectoslocales: 30(75%); rubor 17 (42.5%); tumefacción (menos 20 mm); 13 (32.5%); calor local 11 (27.5%). Efectos generales: fiebre: 37 (92.5%) llanto fuerte y persistente: 32(80%); irritabilidad: 23 (57.5%); hiporreactividad 16 (40%), anorexia 8 (20%); Inmunogenicidad: antes de la 1ª dosis; antitetánica IgG (+) 38/40 (95%), anti-difteria (+) IgG 29/40 (72.5%); anti-HBsAg 0/40 (0%) negativos. Respuesta post-vacuna pentacomb. (7m. edad): antitetánica IgG 14/14 (100%) (+); anti-difteria IgG 12/14 (83%) (+); anti-HBsAg 14/14 (100%) positivos. Se evidencia la reactogenicidad de grado variable y decreciente. Niveles de anticuerpos de los componentes DT, satisfactorios y laHep B excelentes.

The combined cellular pentavalent vaccine is one the greatest achievements of human kind in the 20th century and is still successful in the 21st century. It is made up of fivecomponents and protects against the following diseases: diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae type b. The vaccine provides specific active immunization against infections caused by Corynebacterium diphtheriae, Clostridium tetani, Bordetella pertussis, Haemophilus influenzae type B and the Hepatitis B virus in children from six weeks of age. In Paraguay, it has been used since 2002 through the Widened Program of Immunization (PAI in Spanish) of the Ministry of Public Health. Theobjective of this work was to determine the secondary reactoinmunogenicity to the primary combined pentavalent vaccination in children attending the District Hospital of Lambaré, Paraguay in 2007 and 2008. This is a longitudinal, prospective observational study to evaluate the secondary effects and immune-specific aspects of the Berna DTPw- HepB-Hib combined pentavalent vaccine (QUINVAXEMTM) applied to breastfed babies under one year old, of both sexes, all races, origins and nutrition statuses in the Hospitalof Lambaré. The vaccination was free, according to PAI's guidelines and by consecutive sampling previous written consent of the parents, at 2 months of age. Data were collected at baseline an post-vaccination after one month and a third dose. In a total population of 40 breastfed babies, good nutrition was found in 36 (90%). Local effectswere seen in 30 (75%) distributed as follows: blush in 17 (42.5%), tumefaction (less than 20 mm) in 13 (32.5%) and local heat in 11 (27.5%). General effects were distributed as follows: fever in 37 (92.5%), loud and persistent cry in 32 (80%),irritability in 23 (57.5%), hyporeactivity in 16 (40%), anorexia in 8 (20%), hypotonicity and allergy, 2 each (5%), convulsions and paralysis in none. The effects are an average after the three...