Browsing by Author "Schilling, Andrea"
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Item Adolescentes encuentran fácil tomar sus propias muestras para estudio de infecciones de transmisión sexual(Sociedad Chilena de Infectología, 2017) Huneeus, Andrea; Fernández, Mario; Schilling, Andrea; Parra, Paulina; Zakharova, AleksandraBackground: As alternative for patients that fear genital examination, we assessed adolescent's comfort and ease with self-collected samples for nucleic acid amplification testing for sexually transmitted infections. Patients and Methods: Sexually active Chilean adolescents and youth under 25 years (174 males and 117 females) were enrolled. Females used self-collected vaginal swabs and males collected first-stream urine. A satisfaction survey evaluating self-sampling system was applied. Results: Self-collection was considered easy in 99.3% of the interviewees (CI 95% 0.88-0.98). In women, 79.3% preferred vaginal self-collected samples than pelvic exam (CI 95% 0.73-0.85). In men, 80.3% preferred self-collected first-stream urine to urethral swabs (CI 95% 0.73-0.87). Assuming that self-collected sampling were available, 89.6% of women (CI 95% 0.85-0.94) and 93.2% of men (CI 95% 0.89-0.98) would be prone to be tested more often. Ease of self-collected sampling is not associated with age, gender, educational level or poverty. Conclusions: Chile currently does not have sexually transmitted infections surveillance or screening programs for youth and adolescents. Given self-collected sampling's good acceptability, it could be successfully used when these programs are implemented.Item Beneficios no anticonceptivos de 0,02 mg de etinilestradiol/2 mg de acetato de clormadinona administrados en un régimen de 24+4 días(2011) Zahradnik, Hans; Hanjalic, Aida; Schilling, AndreaObjetivo: Demostrar la influencia sobre las molestias emocionales y físicas (beneficios no anticonceptivos) experimentadas durante el primer año de uso de un anticonceptivo oral combinado (AOC) que contiene 0,02 mg de etinilestradiol (EE) y 2 mg de acetato de clormadinona (ACM) administrado en un régimen de 24 + 4 días de placebo. Diseño del estudio: Análisis adicional de las sensaciones subjetivas registradas en los diarios de 1665 participantes de un estudio de Fase III multicéntrico, no controlado, de administración múltiple, después de 13 ciclos de EE/ACM en un régimen de administración de 24 + 4 días, publicado previamente. Resultados: Se informó de menor frecuencia de molestias emocionales y físicas en el ciclo de medicación 13 en comparación con los datos en la admisión y en el ciclo 1. La incidencia de ánimo depresivo se redujo en 84,5% y 72,2% respectivamente, y la irritabilidad en 87,3% y 66,0%. Las cefaleas se redujeron en 75,5% y 74,7%, las molestias mamarias en 77,1% y 66,1%, y la dismenorrea preexistente en 77,9% y 67,6% respectivamente. El abandono prematuro del estudio a causa de las molestias fue marginal, y el perfil del sangrado fue aceptable. Conclusiones: Un AOC de baja dosis que contiene 0,02 mg de EE + 2 mg de ACM, administrado en un régimen de 24 + 4 días, reduce significativamente la mayor parte de las molestias emocionales y físicas que se presentan durante los ciclos espontáneos de las mujeres, y se combina con un adecuado perfil de sangrado.Publication Cervical artery dissection in postpartum women after cesarean and vaginal delivery(2022) Urrutia, Francisca; Mazzon, Enrico; Brunser, Alejandro; Díaz, Violeta; Calderon, Juan; Stecher, Ximena; Bernstein, Tomas; Zuñiga, Paulo; Schilling, Andrea; Muñoz, PaulaBackground and aims: Cervical artery dissection (CAD) is an infrequent but potentially disabling and fatal disease, accounting for up to 25 % of strokes in young adults. Pregnancy-related hormonal changes and increased hemodynamic stress on artery walls during vaginal delivery have been associated to CAD. We aim to describe a series of women presenting CAD during postpartum (PP) after cesarean and vaginal delivery. Methods: CAD women admitted to one hospital in Santiago, Chile, between July 2018 and October 2020 were included in a prospective cohort. Demographic, clinical and imaging data were registered for the PP group. Results: Sixty-seven women were diagnosed with CAD, from which 10 were PP. Seven women had cesarean section and 3 had vaginal delivery. They presented CAD related symptoms after a median of 10.5 (IQR 5-15) days from delivery. All of them had headache as initial symptom, 9 presented cervical pain and 8 had a family history of stroke. Four patients presented preeclampsia during pregnancy. Acute treatment consisted mostly in antiplatelet agents and analgesics. None of these patients had a CAD related stroke. Demographic, clinical and imaging characteristics of these women with CAD during PP are described. Conclusions: This case series underpins the importance of clinical suspicion of CAD after delivery, highlighting the fact that CAD is not limited to women with vaginal delivery, thus alternative causes beyond acute hemodynamic stress could be involved. Further research is required to determine genetic components, along with deeper knowledge of modulating factors related to CAD in this setting.Item Coadministration of a 9-Valent Human Papillomavirus Vaccine With Meningococcal and Tdap Vaccines(Elsevier, 2001) Schilling, Andrea; Macias Parra, Mercedes; Gutierrez, Maricruz; Restrepo, Jaime; Ucros, Santiago; Herrera, Teobaldo; Engel, Eli; Huicho, Luis; Shew, Marcia; Maansson, Roger; Caldwell, Nicole; Luxembourg, Alain; Sobanjo ter Meulen, AjokeBACKGROUND: This study in 11- to 15-year-old boys and girls compared the immunogenicity and abstract safety of GARDASIL 9 (9-valent human papillomavirus [9vHPV] vaccine) administered either concomitantly or nonconcomitantly with 2 vaccines routinely administered in this age group (Menactra [MCV4; Neisseria meningitidis serotypes A/C/Y/W-135] or Adacel [Tdap; diphtheria/tetanus/acellular pertussis]). METHODS: Participants received 9vHPV vaccine at day 1 and months 2 and 6; the concomitant group (n = 621) received MCV4/Tdap concomitantly with 9vHPV vaccine at day 1; the nonconcomitant group (n = 620) received MCV4/Tdap at month 1. Antibodies to HPV-, MCV4-, and Tdap-relevant antigens were determined. Injection-site and systemic adverse events (AEs) were monitored for 15 days after any vaccination; serious AEs were monitored throughout the study. RESULTS: The geometric mean titers for all HPV types in 9vHPV vaccine 4 weeks after dose 3, proportion of subjects with a fourfold rise or greater in titers for 4 N meningitidis serotypes 4 weeks after injection with MCV4, proportion of subjects with antibody titers to diphtheria and tetanus $0.1 IU/mL, and geometric mean titers for pertussis antigens 4 weeks after injection with Tdap were all noninferior in the concomitant group compared with the nonconcomitant group. Injection-site swelling occurred more frequently in the concomitant group. There were no vaccine-related serious AEs. CONCLUSIONS: Concomitant administration of 9vHPV vaccine with MCV4/Tdap was generally well tolerated and did not interfere with the antibody response to any of these vaccines. This strategy would minimize the number of visits required to deliver each vaccine individually.Item Criterios Médicos de elegibilidad para el uso de anticonceptivos de la OMS(Sociedad Chilena de Obstetricia y Ginecología, 2017) Capella, Daniela; Schilling, Andrea; Villaroel., ClaudioIntroduction: The "Medical Eligibility Criteria for Contraceptive Use" published by the World Health Organization (WHO) is a guide for the correct choice and use of the contraceptive methods in many different health conditions. In this document we will review the main changes made in the fifth and last edition of this guide published in English in 2015. Development: The modifications of this last edition are the addition of new contraceptive methods and the modification of the category of the recommendation for some health conditions. It adds the medroxiprogesterone acetate subcutaneous injection, the progesterone vaginal ring, the subcutaneous contraceptive implant sinoimplant(II)® and ulipristal acetate as emergency contraception. There are modifications of the recommendations for breastfeeding women, allowing the use of some progestin only methods since the immediate postpartum, with the exception of medroxiprogesterone acetate because it delivers a high dose of the steroid and the levonorgestrel intrauterine device that follows the same recommendations as the copper intrauterine device. There are also modifications in the recommendations for the use of combined contraceptives in the first 42 days postpartum, with more restrictions for non-breastfeeding women. Finally, on the use of antiretroviral therapy drugs, there were changes of some categories and a detailed categorization for each drug. Conclusion: It is necessary for health care providers to know these changes in order to deliver a quality care to contraception users.Publication Disparities in Stroke Incidence Over Time by Sex and Age in Latin America and the Caribbean Region 1997 to 2021: A Systematic Review and Meta-Analysis(2023) Nuñez, Marilaura; Delfino, Carlos; Asenjo, Claudia; Schilling, Andrea; Lavados, Pablo; Anderson, Craig; Munoz Venturelli, PaulaBackground High-income country studies show unfavorable trends in stroke incidence (SI) in younger populations. We aimed to estimate temporal change in SI disaggregated by age and sex in Latin America and the Caribbean region. Methods and Results A search strategy was used in MEDLINE, WOS, and LILACS databases from 1997 to 2021, including prospective population-based observational studies with first-ever stroke incidence in Latin America. Reports without data broken down by age and sex were excluded. Risk of bias was assessed with The Joanna Briggs Institute's guide. The main outcomes were incidence rate ratio and relative temporal trend ratio of SI, comparing time periods before 2010 with after 2010. Pooled relative temporal trend ratios considering only studies with 2 periods in the same population were calculated by random-effects meta-analysis. Meta-regression analysis was used to evaluate incidence rate determinants. From 9242 records identified, 6 studies were selected including 4483 first-ever stroke in 4 101 084 individuals. Crude incidence rate ratio in younger subjects (<55 years) comparing before 2010:after 2010 periods showed an increase in SI in the past decade (incidence rate ratio, 1.37 [95% CI, 1.23-1.50]), in contrast to a decrease in older people during the same period (incidence rate ratio, 0.83 [95% CI, 0.76-0.89]). Overall relative temporal trend ratio (<55:≥55 years) was 1.65 (95 CI%, 1.50-1.80), with higher increase in young women (pooled relative temporal trend ratio, 3.08 [95% CI, 1.18-4.97]; P for heterogeneity <0.001). Conclusions An unfavorable change in SI in young people, especially in women, was detected in population-based studies in the past decade in Latin America and the Caribbean. Further investigation of the explanatory variables is required to ameliorate stroke prevention and inform local decision-makers. Registration URL: https://www.crd.york.ac.uk/prospero/ Identifier: CRD42022332563.Publication Inactivated Vaccine-Induced SARS-CoV-2 Variant-Specific Immunity in Children(2022) Soto, Jorge; Melo, Felipe; Gutierrez, Cristián; Schultz, Bárbara; Berríos, Roslye; Rivera, Daniela; Piña, Alejandro; Hoppe, Guillermo; Duarte, Luisa; Vázquez, Yaneisi; Moreno, Daniela; Ríos, Mariana; Palacios, Pablo; Garcia, Richard; Santibañez, Álvaro; Pacheco, Gaspar; Mendez, Constanza; Andrade, Catalina; Silva, Pedro; Diethelm, Benjamín; Astudillo, Patricio; Calvo, Mario; Cárdenas, Antonio; González, Marcela; Goldsack, Macarena; Gutiérrez, Valentina; Potin, Marcela; Schilling, Andrea; Tapia, Lorena; Twele, Loreto; Villena, Rodolfo; Grifoni, Alba; Sette, Alessandro; Weiskopf, Daniela; Fasce, Rodrigo; Fernández, Jorge; Mora, Judith; Ramírez, Eugenio; Gaete, Aracelly; Acevedo, Mónica; Valiente, Fernando; Soto, Ricardo; Retamal, Angello; Muñoz, Nathalia; PedCoronaVac03CL Study Group; Meng, Xing; Xin, Qianqian; Alarcón, Eduardo; González, José; Le Corre, Nicole; Álvarez, María; González, Pablo; Abarca, Katia; Perret, Cecilia; Carreño, Leandro; Bueno, Susan; Kalergisa, AlexisMultiple vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been evaluated in clinical trials. However, trials addressing the immune response in the pediatric population are scarce. The inactivated vaccine CoronaVac has been shown to be safe and immunogenic in a phase 1/2 clinical trial in a pediatric cohort in China. Here, we report interim safety and immunogenicity results of a phase 3 clinical trial for CoronaVac in healthy children and adolescents in Chile. Participants 3 to 17 years old received two doses of CoronaVac in a 4-week interval until 31 December 2021. Local and systemic adverse reactions were registered for volunteers who received one or two doses of CoronaVac. Whole-blood samples were collected from a subgroup of 148 participants for humoral and cellular immunity analyses. The main adverse reaction reported after the first and second doses was pain at the injection site. Four weeks after the second dose, an increase in neutralizing antibody titer was observed in subjects relative to their baseline visit. Similar results were found for activation of specific CD4+ T cells. Neutralizing antibodies were identified against the Delta and Omicron variants. However, these titers were lower than those for the D614G strain. Importantly, comparable CD4+ T cell responses were detected against these variants of concern. Therefore, CoronaVac is safe and immunogenic in subjects 3 to 17 years old, inducing neutralizing antibody secretion and activating CD4+ T cells against SARS-CoV-2 and its variants. (This study has been registered at ClinicalTrials.gov under no. NCT04992260.) IMPORTANCE This work evaluated the immune response induced by two doses of CoronaVac separated by 4 weeks in healthy children and adolescents in Chile. To date, few studies have described the effects of CoronaVac in the pediatric population. Therefore, it is essential to generate knowledge regarding the protection of vaccines in this population. Along these lines, we reported the anti-S humoral response and cellular immune response to several SARS-CoV-2 proteins that have been published and recently studied. Here, we show that a vaccination schedule consisting of two doses separated by 4 weeks induces the secretion of neutralizing antibodies against SARS-CoV-2. Furthermore, CoronaVac induces the activation of CD4+ T cells upon stimulation with peptides from the proteome of SARS-CoV-2. These results indicate that, even though the neutralizing antibody response induced by vaccination decreases against the Delta and Omicron variants, the cellular response against these variants is comparable to the response against the ancestral strain D614G, even being significantly higher against Omicron.Item Preguntas frecuentes respecto a la vacuna contra el virus papiloma humano(2018) Schilling, AndreaEn este artículo práctico, en base a preguntas y respuestas, se abordan las principales consultas formuladas a los especialistas, tales como ¿Porqué vacunar contra VPH? ¿Composición de la vacuna? ¿Cuáles son su eficacia y seguridad? ¿Deben vacunarse varones? y varias otras.Item Prevalence of Chlamydia Trachomatis, Neisseria Gonorrhoeae, and Trichomonas Vaginalis Infection in Chilean Adolescents and Young Adults(2018) Huneeus, Andrea; Schilling, Andrea; Fernandez, Mario I.Study objective: To determine the prevalence of Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis infection in sexually active Chilean adolescents and young adults. A comparative analysis was performed between genders to identify demographic, clinical, and sexual behavior characteristics to predict the occurrence of C trachomatis. Design: Analytical observational study. Setting: Santiago, Chile. Participants: Two hundred eighty-six sexually active volunteers aged 24 years or younger (171 female and 115 male); 82.9% (237/286) of them were classified as having high socioeconomic status. Interventions: Confidential survey and self-collected samples (urine for men and vaginal swabs for women). Main outcome measures: Prevalence, demographic characteristics, symptoms, and sexual behavior characteristics. Results: The prevalence rate of C trachomatis was 8.7% (10/115) in men and 8.8% (15/171) in women (P = .58). N gonorrhoeae was detected in 1 subject, whereas no T vaginalis cases were detected. In multivariate analysis, having some college education was protective (odds ratio [OR], 0.28; 95% confidence interval [CI], 0.09-0.89), whereas having a higher number of sexual partners was a risk factor (OR, 1.19; 95% CI, 1.1-1.3) for C trachomatis infection. The latter was also predicted by postcoital bleeding (OR, 4.6; 95% CI, 1.30-16.23) in the female model. Conclusion: C trachomatis infection rates were similar between both genders. Protective characteristics for the occurrence of this infection were having some college education, lower number of sexual partners, and if female, the absence of postcoital bleeding. This study highlights the importance of C trachomatis screening among the Chilean affluent population younger than 25 years. However, further studies are needed in a more diverse and representative sample to recommend universal screening in Chilean adolescents and young adults.Item Prevalencia y manejo de condilomas en población consultante en Chile: estudio “DIACON”(2019) Schilling, Andrea; Huneeus, Andrea; Masso, Alejandra; Rivera, Francisca; Cavada, GabrielIntroducción: Los condilomas o verrugas genitales (VG) son la infección de transmisión sexual (ITS) más diagnosticada en los centros de ITS en Chile, pero no existen estadísticas poblacionales. Objetivos: Describir la prevalencia de VG en pacientes de 18-60 años que acuden a consulta ambulatoria de dermatología, ginecología y urología; características demográficas de los pacientes y prácticas de diagnóstico y tratamiento. Material y Métodos: A una muestra de especialistas chilenos estratificados por región, población y sexo de pacientes se les proporcionó un diario de registro y aplicó un cuestionario. Resultados: Prevalencia VG grupo total: 2,4%; en grupo etario 18-34 años: 3,7%; en grupo etario 35-60 años: 1,29% (p = 0,0000). La edad media de los pacientes con VG fue 29,4 años en mujeres y 32,7 años en hombres (p = 0,019); la distribución por edad fue diferente según sexo y sistema de salud. La inspección visual fue el método diagnóstico más frecuente y la crema de imiquimod el tratamiento más común. Hubo diferencias en el uso de herramientas diagnósticas y terapéuticas según sexo del paciente, especialidad del médico y sistema de salud. Conclusiones: Existe una alta prevalencia de VG, que debería ser tomada en cuenta para planificar las intervenciones de salud pública para abordar este problema.Publication Safety and Non-Inferiority Evaluation of Two Immunization Schedules with an Inactivated SARS-CoV-2 Vaccine in Adults: A Randomized Clinical Trial(2022) Abarca, Katia; Iturriaga, Carolina; Urzúa, Marcela; Le Corre, Nicole; Pineda, Augusto; Fernández, Carolina; Domínguez, Angélica; González, Pablo; Bueno, Susan; Donato, Paulina; Espinoza, Pilar; Fuentes, Daniela; González, Marcela; Guzmán, Paula; Muñoz Venturelli, Paula; Pérez, Carlos; Potin, Marcela; Rojas, Álvaro; González, José; Gálvez, Nicolás; Aguirre, Francisca; Aljaro, Sofía; Bátiz, Luis; Campisto, Yessica; Cepeda, Mariela; Cortés, Aarón; López, Sofía; Pérez, María; Schilling, Andrea; Kalergis, Alexis; On behalf of the CoronaVac CL Study GroupSeveral vaccines have been developed to control the COVID-19 pandemic. CoronaVac®, an inactivated SARS-CoV-2 vaccine, has demonstrated safety and immunogenicity, preventing severe COVID-19 cases. We investigate the safety and non-inferiority of two immunization schedules of CoronaVac® in a non-inferiority trial in healthy adults. A total of 2302 healthy adults were enrolled at 8 centers in Chile and randomly assigned to two vaccination schedules, receiving two doses with either 14 or 28 days between each. The primary safety and efficacy endpoints were solicited adverse events (AEs) within 7 days of each dose, and comparing the number of cases of SARS-CoV-2 infection 14 days after the second dose between the schedules, respectively. The most frequent local AE was pain at the injection site, which was less frequent in participants aged ≥60 years. Other local AEs were reported in less than 5% of participants. The most frequent systemic AEs were headache, fatigue, and myalgia. Most AEs were mild and transient. There were no significant differences for local and systemic AEs between schedules. A total of 58 COVID-19 cases were confirmed, and all but 2 of them were mild. No differences were observed in the proportion of COVID-19 cases between schedules. CoronaVac® is safe, especially in ≥60-year-old participants. Both schedules protected against COVID-19 hospitalization.Item Safety Profile of the 9-Valent HPV Vaccine: A Combined Analysis of 7 Phase III Clinical Trials(American Academy of Pediatrics, 2016) Edson, Moreira; Block, Stan; Ferris, Daron; Giuliano, Anna; Iversen, Ole-Erik; Joura, Elmar; Kosalaraksa, Pope; Schilling, Andrea; Van Damme, Pierre; Bornstein, Jacob; Bosch, Xavier; Pils, Sophie; Cuzick, Jack; Garland, Suzanne; Huh, Warner; Kjaer, Susanne; Qi, Hong; Hyatt, Donna; Martin, Jason; Moeller, Erin; Ritter, Michael; Baudin, Martine; Luxembourg, AlainOBJECTIVES: The overall safety profile of the 9-valent human papillomavirus (9vHPV) vaccine was evaluated across 7 Phase III studies, conducted in males and females (nonpregnant at entry), 9 to 26 years of age. METHODS: Vaccination was administered as a 3-dose regimen at day 1, and months 2 and 6. More than 15 000 subjects received ≥1 dose of 9vHPV vaccine. In 2 of the studies, >7000 control subjects received ≥1 dose of quadrivalent HPV (qHPV) vaccine. Serious and nonserious adverse events (AEs) and new medical conditions were recorded throughout the study. Subjects testing positive for pregnancy at day 1 were not vaccinated; those who became pregnant after day 1 were discontinued from further vaccination until resolution of the pregnancy. Pregnancies detected after study start (n = 2950) were followed to outcome. RESULTS: The most common AEs (≥5%) experienced by 9vHPV vaccine recipients were injection-site AEs (pain, swelling, erythema) and vaccine-related systemic AEs (headache, pyrexia). Injection-site AEs were more common in 9vHPV vaccine than qHPV vaccine recipients; most were mild-to-moderate in intensity. Discontinuations and vaccine-related serious AEs were rare (0.1% and <0.1%, respectively). Seven deaths were reported; none were considered vaccine related. The proportions of pregnancies with adverse outcome were within ranges reported in the general population. CONCLUSIONS: The 9vHPV vaccine was generally well tolerated in subjects aged 9 to 26 years with an AE profile similar to that of the qHPV vaccine; injection-site AEs were more common with 9vHPV vaccine. Its additional coverage and safety profile support widespread 9vHPV vaccination.Item Three-Year Follow-up of 2-Dose Versus 3-Dose HPV Vaccine(2021) Bornstein, Jacob; Roux, Surita; Kjeld, Lone; Huang, Li-Min; Dobson, Simon; Pitisuttithum, Punnee; Diez, Javier; Schilling, Andrea; Ariffin, Hany; Tytus, Richard; Rupp, Richard; Senders, Shelly; Engel, Eli; Ferris, Daron; Kim, Yae-Jean; Tae, Young; Kurugol, Zafer; Bautista, Oliver; Nolan, Katrina; Sankaranarayanan, Sandhya; Saah, Alfred; Luxembourg, Alain;BACKGROUND AND OBJECTIVES: Human papillomavirus (HPV) antibody responses to the 9-valent abstract human papillomavirus (9vHPV) vaccine among girls and boys (aged 9–14 years) receiving 2- dose regimens (months 0, 6 or 0, 12) were noninferior to a 3-dose regimen (months 0, 2, 6) in young women (aged 16–26 years) 4 weeks after last vaccination in an international, randomized, open-label trial (NCT01984697). We assessed response durability through month 36. METHODS: Girls received 2 (months 0 and 6 [0, 6]: n = 301; months 0 and 12 [0, 12]: n = 151) or 3 doses (months 0,2, and 6 [0, 2, 6]: n = 301); boys received 2 doses ([0, 6]: n = 301; [0, 12]: n = 150); and young women received 3 doses ([0, 2, 6]: n = 314) of 9vHPV vaccine. Anti-HPV geometric mean titers (GMTs) were assessed by competitive Luminex immunoassay (cLIA) and immunoglobulin G-Luminex immunoassay (IgG-LIA) through month 36. RESULTS: Anti-HPV GMTs were highest 1 month after the last 9vHPV vaccine regimen dose, decreased sharply during the subsequent 12 months, and then decreased more slowly. GMTs 2 to 2.5 years after the last regimen dose in girls and boys given 2 doses were generally similar to or greater than GMTs in young women given 3 doses. Across HPV types, most boys and girlswho received 2 doses (cLIA: 81%–100%; IgG-LIA: 91%–100%) and young women who received 3 doses (cLIA: 78%–98%; IgG-LIA: 91%–100%) remained seropositive 2 to 2.5 years after the last regimen dose. CONCLUSIONS: Antibody responses persisted through 2 to 2.5 years after the last dose of a 2-dose 9vHPV vaccine regimen in girls and boys. In girls and boys, antibody responses generated by 2 doses administered 6 to 12 months apart may be sufficient to induce high-level protective efficacy through at least 2 years after the second dose.