RESUMO
Human cytomegalovirus (HCMV) can cause congenital infections, which are a leading cause of childhood disabilities. Since the rate of maternal-fetal transmission is much lower in naturally infected (HCMV-seropositive) women, we hypothesize that a vaccine candidate capable of eliciting immune responses analogous to those of HCMV-seropositive subjects may confer protection against congenital HCMV. We have previously described a replication-defective virus vaccine based on strain AD169 (D. Wang, D. C. Freed, X. He, F. Li, et al., Sci Transl Med 8:362ra145, 2016, https://doi.org/10.1126/scitranslmed.aaf9387). The vaccine, named V160, has been shown to be safe and immunogenic in HCMV-seronegative human subjects, eliciting both humoral and cellular immune responses (S. P. Adler, S. E. Starr, S. A. Plotkin, S. H. Hempfling, et al., J Infect Dis 220:411-419, 2019, https://doi.org/10.1093/infdis/171.1.26). Here, we further showed that sera from V160-immunized HCMV-seronegative subjects have attributes similar in quality to those from seropositive subjects, including high-avidity antibodies to viral antigens, coverage against a panel of genetically distinct clinical isolates, and protection against viral infection in diverse types of human cells in culture. More importantly, vaccination appeared efficient in priming the human immune system, inducing memory B cells in six V160 recipients at frequencies comparable to those of three HCMV-seropositive subjects. Our results demonstrate the ability of V160 to induce robust and durable humoral memory responses to HCMV, justifying further clinical evaluation of the vaccine against congenital HCMV.IMPORTANCEIn utero HCMV infection can lead to miscarriage or childhood disabilities, and an effective vaccine is urgently needed. Since children born to women who are seropositive prior to pregnancy are less likely to be affected by congenital HCMV infection, it has been hypothesized that a vaccine capable of inducing an immune response resembling the responses in HCMV-seropositive women may be effective. We previously described a replication-defective virus vaccine that has been demonstrated safe and immunogenic in HCMV-seronegative subjects. Here, we conducted additional analyses to show that the vaccine can induce antibodies with functional attributes similar to those from HCMV-seropositive subjects. Importantly, vaccination can induce long-lived memory B cells at frequencies comparable to those seen in HCMV-seropositive subjects. We conclude that this vaccine is a promising candidate that warrants further clinical evaluation for prevention of congenital HCMV.
Assuntos
Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/prevenção & controle , Vacinas contra Citomegalovirus/imunologia , Citomegalovirus/imunologia , Imunidade Humoral/imunologia , Imunização , Adulto , Idoso , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Antígenos Virais/sangue , Linhagem Celular , Infecções por Citomegalovirus/congênito , Infecções por Citomegalovirus/virologia , Método Duplo-Cego , Feminino , Humanos , Imunidade Celular , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Masculino , Pessoa de Meia-Idade , Estados Unidos , Vacinação , Replicação Viral , Adulto JovemRESUMO
BACKGROUND: A conditionally replication-defective human cytomegalovirus (CMV) vaccine (V160) derived from AD169 and genetically engineered to express CMV pentameric complex (gH/gL/pUL128/pUL130/pUL131) was developed and evaluated for phase 1 vaccine safety and immunogenicity in CMV-seronegative and CMV-seropositive adults. METHODS: Subjects received 3 doses of V160 or placebo on day 1, month 1, and month 6. Four vaccine dose levels, formulated with or without aluminum phosphate adjuvant, were evaluated. Injection-site and systemic adverse events (AEs) and vaccine viral shedding were monitored. CMV-specific cellular and humoral responses were measured by interferon-gamma ELISPOT and virus neutralization assay up to 12 months after last dose. RESULTS: V160 was generally well-tolerated, with no serious AEs observed. Transient, mild-to-moderate injection-site and systemic AEs were reported more frequently in vaccinated subjects than placebo. Vaccine viral shedding was not detected in any subject, confirming the nonreplicating feature of V160. Robust neutralizing antibody titers were elicited and maintained through 12 months postvaccination. Cellular responses to structural and nonstructural viral proteins were observed, indicating de novo expression of viral genes postvaccination. CONCLUSIONS: V160 displayed an acceptable safety profile. Levels of neutralizing antibodies and T-cell responses in CMV-seronegative subjects were within ranges observed following natural CMV infection. CLINICAL TRIAL REGISTRATION: . NCT01986010.
Assuntos
Infecções por Citomegalovirus/imunologia , Vacinas contra Citomegalovirus/imunologia , Citomegalovirus/imunologia , Replicação Viral/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adolescente , Adulto , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Método Duplo-Cego , ELISPOT/métodos , Feminino , Humanos , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Imunização/métodos , Masculino , Pessoa de Meia-Idade , Linfócitos T/imunologia , Vacinação/métodos , Eliminação de Partículas Virais/imunologia , Adulto JovemRESUMO
To study the dynamics of body mass changes in hand reared clouded leopards, we analyzed 3,697 weight data points during the first 3 months of life in 49 cubs from 24 zoo-born litters from 2003 through 2012. All cubs were fed the same formula mixture after a similar weaning protocol. The hand rearing process was divided into three periods based on feeding protocols: Stage 1: formula only (Days 1-28; Day 0 = day of birth); Stage 2, formula supplemented with protein (e.g., turkey baby food; Days 29-42); Stage 3, formula in decreasing amounts supplemented with meat (chicken and/or beef; Days 43-90). Weights at birth were 11.2% higher (P < 0.001) for males (n = 29) than females (n = 20). Daily weight gain was slowest (P < 0.05) during Stage 1 when cubs were fed straight formula only and fastest during Stage 3 when provided a mixture of formula and meat. Mean growth rate (± SD) during hand rearing differed (P < 0.05) by gender, being 34.6 ± 1.4 g/day for male and 30.0 ± 1.2 g/day for female cubs. Eighteen cubs (37%) exhibited mild to severe diarrhea during the study; however, palliative treatment resulted in similar (P > 0.05) growth and weaning weights compared to healthy counterparts. These are the first data documenting, on a large scale, the growth patterns for zoo born, hand reared clouded leopard cubs. Findings are valuable as an aid in managing this rare species, including for helping identify early onset of medical issues and further determining key factors regulating the first 3 months of development.
Assuntos
Animais de Zoológico/fisiologia , Felidae/fisiologia , Aumento de Peso/fisiologia , Criação de Animais Domésticos , Animais , Animais Recém-Nascidos , Animais de Zoológico/crescimento & desenvolvimento , Felidae/crescimento & desenvolvimento , Feminino , Masculino , Fatores Sexuais , DesmameRESUMO
BACKGROUND: A vaccine that prevents cytomegalovirus (CMV) infection in women could reduce the incidence of congenital CMV infection, a major cause of neurodevelopmental disability. We aimed to assess the safety and efficacy of a replication-defective investigational CMV vaccine, V160, in CMV-seronegative women. METHODS: This phase 2b, randomised, double-blind, placebo-controlled study was conducted at 90 sites in seven countries (USA, Finland, Canada, Israel, Spain, Russia, and Australia). Eligible participants were generally healthy, CMV-seronegative, non-pregnant, 16-35-year-old women of childbearing potential with exposure to children aged 5 years or younger. Participants were randomly assigned using central randomisation via an interactive response technology system 1:1:1 to one of three groups: V160 three-dose regimen (V160 at day 1, month 2, and month 6), V160 two-dose regimen (V160 on day 1, placebo at month 2, and V160 at month 6), or placebo (saline solution at day 1, month 2, and month 6). The primary outcomes were the efficacy of three doses of V160 in reducing the incidence of primary CMV infection during the follow-up period starting 30 days after the last dose of vaccine using a fixed event rate design, and the safety and tolerability of the two-dose and three-dose V160 regimens. We planned to test the efficacy of a two-dose regimen of V160 in reducing the incidence of primary CMV infection only if the primary efficacy hypothesis was met. Analyses for the primary efficacy endpoint were performed on the per-protocol efficacy population; safety analyses included all randomly assigned participants who received study vaccine. The primary efficacy hypothesis was tested at prespecified interim and final analyses. The study was ongoing and efficacy data continued to accrue at the time of final testing of the primary efficacy hypothesis. Vaccine efficacy was re-estimated after final testing of the primary efficacy hypothesis based on all available efficacy data at end of study. This trial is registered at ClinicalTrials.gov (NCT03486834) and EudraCT (2017-004233-86) and is complete. FINDINGS: Between April 30, 2018, and Aug 30, 2019, 7458 participants were screened, of whom 2220 were randomly assigned to the V160 three-dose group (n=733), V160 two-dose group (n=733), or placebo group (n=734). A total of 523 participants in the V160 three-dose group and 519 in the placebo group were included in the final hypothesis testing. Of these, there were 11 cases of CMV infection in the V160 three-dose group and 20 cases in the placebo group. The vaccine efficacy for the V160 three-dose group was 44·6% (95% CI -15·2 to 74·8) at the final testing of the primary efficacy hypothesis, a result corresponding to failure to demonstrate the primary efficacy hypothesis. On the basis of this result, the study was terminated for futility. The re-estimate of vaccine efficacy for the V160 three-dose group based on all available efficacy data at end of study (556 participants in the V160 three-dose group and 543 in the placebo group) was 42·4% (95% CI -13·5 to 71·1). A total of 728 participants in the V160 three-dose group, 729 in the V160 two-dose group, and 732 in the placebo group were included in the safety analyses. The most common solicited injection-site adverse event was injection-site pain (680 [93%] in the V160 three-dose group, 659 [90%] in the V160 two-dose group, and 232 [32%] in the placebo group). The most common solicited systemic adverse event was fatigue (457 [63%] in the V160 three-dose group, 461 [63%] in the V160 two-dose group, and 357 [49%] in the placebo group). No vaccine-related serious adverse events or deaths were reported. INTERPRETATION: V160 was generally well tolerated and immunogenic; however, three doses of the vaccine did not reduce the incidence of primary CMV infection in CMV-seronegative women compared with placebo. This study provides insights into the design of future CMV vaccine efficacy trials, particularly for the identification of CMV infection using molecular assays. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA (MSD).
Assuntos
Infecções por Citomegalovirus , Vacinas contra Citomegalovirus , Vacinas , Criança , Humanos , Feminino , Adolescente , Adulto Jovem , Adulto , Citomegalovirus , Imunização , Infecções por Citomegalovirus/prevenção & controle , Método Duplo-Cego , Imunogenicidade da VacinaRESUMO
OBJECTIVES: To evaluate the efficacy and safety of molnupiravir for intra-household post-exposure prophylaxis (PEP) of COVID-19. METHODS: MOVe-AHEAD was a randomized, controlled, double-blind, phase 3 trial comparing molnupiravir (800 mg twice daily for 5 days) with placebo. Eligible participants were adult, unvaccinated, asymptomatic household contacts of patients with laboratory-confirmed COVID-19. The primary efficacy endpoint was the incidence of COVID-19 through day 14 in modified intention-to-treat (MITT) participants (those who received ≥1 dose of study intervention) without detectable SARS-CoV-2 at baseline, termed the MITT-VN population. Superiority of molnupiravir was prespecified as a stratified one-sided p-value of <0.0249 for the treatment difference in this endpoint. RESULTS: The MITT population comprised 763 participants randomized to molnupiravir and 764 to placebo; 83.6% had anti-SARS-CoV-2 antibodies at baseline. In the MITT-VN population, COVID-19 rates through day 14 were 6.5% with molnupiravir and 8.5% with placebo (one-sided p-value: 0.0848). In the molnupiravir arm, 25/35 of confirmed COVID-19 events (71.4%) occurred after completion of treatment (versus 17/49 [34.7%] for placebo). Adverse event rates were low and similar between molnupiravir and placebo. CONCLUSIONS: Molnupiravir was well-tolerated but did not meet the prespecified superiority criterion, possibly influenced in part by the high pre-existing immunity in the trial population.
RESUMO
Understanding factors that influence reproduction and offspring survival in zoo populations is critical for management of threatened and endangered species. Examination of long-term data (1989-2011) compiled from the Association of Zoos and Aquarium's zoo-managed tiger breeding program provides the basis for a more thorough understanding of reproduction and scientifically based decisions for effective population management in this endangered felid. Biological and management-related factors that could influence tiger breeding success and cub survival were evaluated using logistic mixed models. Breeding success improved with female age until approximately age five, then declined thereafter. Experienced female breeders had greater breeding success than inexperienced females. Litter size was most predictive of cub survival, with average-sized litters (3-4 cubs) experiencing the highest proportional survival. Management-related factors, such as whether the breeding institution had a recent tiger litter and whether both animals were already located at the same institution, also influenced breeding success and cub survival. These results highlight the importance of institutional husbandry experience and the need to retain knowledge through staff turnovers to achieve optimal reproductive success. Using fecal estrogen data, frequency of ovarian cyclicity and mean cycle length did not differ by female age or parity; thus, lack of cyclicity and/or increased cycle duration are not likely explanations for declining breeding success with age. These results provide valuable reproductive information that should improve scientific management of zoo-based tiger populations.