Antigenic Fingerprinting following Primary RSV Infection in Young Children Identifies Novel Antigenic Sites and Reveals Unlinked Evolution of Human Antibody Repertoires to Fusion and Attachment Glycoproteins.

Respiratory Syncytial Virus (RSV) is the major cause of pneumonia among infants. Here we elucidated the antibody repertoire following primary RSV infection and traced its evolution through adolescence and adulthood. Whole genome-fragment phage display libraries (GFPDL) expressing linear and conformational epitopes in the RSV fusion protein (F) and attachment protein (G) were used for unbiased epitope profiling of infant sera prior to and following RSV infection. F-GFPDL analyses demonstrated modest changes in the anti-F epitope repertoires post-RSV infection, while G-GFPDL analyses revealed 100-fold increase in number of bound phages. The G-reactive epitopes spanned the N- and C-terminus of the G ectodomain, along with increased reactivity to the central conserved domain (CCD). Panels of F and G antigenic sites were synthesized to evaluate sera from young children (<2 yr), adolescents (14-18 yr) and adults (30-45 yr) in SPR real-time kinetics assays. A steady increase in RSV-F epitope repertoires from young children to adults was observed using peptides and F proteins. Importantly, several novel epitopes were identified in pre-fusion F and an immunodominant epitope in the F-p27. In all age groups, antibody binding to pre-fusion F was 2-3 folds higher than to post-fusion form. For RSV-G, antibody responses were high following early RSV infection in children, but declined significantly in adults, using either G proteins or peptides. This study identified unlinked evolution of anti-F and anti G responses and supportive evidence for immune pressure driven evolution of RSV-G. These findings could help development of effective countermeasures including vaccines.

Development of an adenovirus-based respiratory syncytial virus vaccine: preclinical evaluation of efficacy, immunogenicity, and enhanced disease in a cotton rat model.

UNLABELLED: The lack of a vaccine against respiratory syncytial virus (RSV) is a challenging and serious gap in preventive medicine. Herein, we characterize the immunogenicity of an adenovirus serotype 5-based RSV vaccine encoding the fusion (F) protein (Ad5.RSV-F) and the protection provided following immunization with Ad5.RSV-F and assess its potential for producing enhanced disease in a cotton rat (CR) model. Animals were immunized intranasally (i.n.) and/or intramuscularly (i.m.) and subsequently challenged with RSV/A/Tracy (i.n.) to assess protection. Robust immune responses were seen in CRs vaccinated with Ad5.RSV-F given i.m. or i.n., and these responses correlated with reduced replication of the virus in noses and lungs after challenge. Neutralizing antibody responses following immunization with a single dose of Ad5.RSV-F at 1 × 10(11) viral particles (v.p.) elicited antibody titers 64- to 256-fold greater than those seen after natural infection. CRs boosted with Ad5.RSV-F i.n. 28 days after an i.m. dose also had significant increases in neutralizing antibody titers. Antibody affinity for different F-protein antigenic sites revealed substantial differences between antibodies elicited by Ad5.RSV-F and those seen after RSV infection; differences in antibody profiles were also seen between CRs given Ad5.RSV-F i.m. and CRs given Ad5.RSV-F i.n. Ad5.RSV-F priming did not result in enhanced disease following live-virus challenge, in contrast to the histopathology seen in CRs given the formalin-inactivated RSV/A/Burnett vaccine. IMPORTANCE: Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in infants and young children and a serious health threat in the immunocompromised and the elderly. Infection severity increased in children in an immunization trial, hampering the over 4-decade-long quest for a successful RSV vaccine. In this study, we show that a genetically engineered RSV-F-encoding adenoviral vector provides protective immunity against RSV challenge without enhanced lung disease in cotton rats (CRs). CRs were vaccinated under a number of different regimens, and the immunity induced by the recombinant adenoviral RSV vaccine administered by use of an intramuscular prime-intranasal boost regimen may provide the best protection for young infants and children at risk of RSV infection, since this population is naive to adenoviral preformed immunity. Overall, this report describes a potential RSV vaccine candidate that merits further evaluation in a phase I clinical study in humans.

Measles humoral and cell-mediated immunity in children aged 5-10 years after primary measles immunization administered at 6 or 9 months of age.

BACKGROUND: Given the high infant measles mortality rate, there is interest in whether a measles immunization regimen beginning at <12 months of age provides lasting immunity. METHODS: Measles-specific immune responses were evaluated in 70 children aged 5-10 years after primary measles vaccine administered at 6, 9, or 12 months. RESULTS: At 5-10 years of age, the stimulation index for measles T-cell proliferation was 11.4 (SE, 1.3), 10.9 (SE, 1.5), and 14.4 (SE 2.1) when the first measles dose was given at 6, 9, or 12 months, respectively. Neutralizing antibody concentration (geometric mean titer [GMT]) in those immunized at 6 months of age was 125 mIU/mL (95% confidence interval [CI], 42-377) in the presence of passive antibodies (PAs) and 335 mIU/mL (95% CI, 211-531) in those without PAs; in those immunized at 9 months, GMTs were 186 mIU/mL (95% CI, 103-335) and 1080 mIU/mL (95% CI, 642-1827) in the presence and absence of PAs, respectively. The GMT was 707 mIU/mL (95% CI, 456-1095) when vaccine was administered at 12 months (P ≤ .04). CONCLUSIONS: Measles-specific T-cell responses were sustained at 5-10 years of age regardless of age at time of primary measles immunization. Neutralizing antibody concentrations were lower in cohorts given the first vaccine dose at 6 months of age and in the presence of PAs; however, responses could be boosted by subsequent doses. Starting measles vaccination at <12 months of age may be beneficial during measles outbreaks or in endemic areas.

Influenza and respiratory syncytial virus (RSV) vaccines for infants: safety, immunogenicity, and efficacy.

Respiratory viral infections in infants and young children frequently cause illness that can easily progress to hospitalization and death. There are currently no licensed vaccines to prevent respiratory viral disease in children younger than 6 months, reflecting safety concerns and the difficulty in inducing effective immune responses in infants. This review discusses vaccines that have been developed, or are currently being developed, against influenza and respiratory syncytial virus, with a focus on studies performed to demonstrate their safety and efficacy, and the impact of immunologic immaturity and maternal antibodies on the infant response to vaccines.

A neutralization assay for respiratory syncytial virus using a quantitative PCR-based endpoint assessment.

BACKGROUND: Few studies have used quantitative polymerase chain reaction (qPCR) as an approach to measure virus neutralization assay endpoints. Its lack of use may not be surprising considering that sample nucleic acid extraction and purification can be expensive, labor-intensive, and rate-limiting. METHODS: Virus/antibody mixtures were incubated for one hour at 37°C and then transferred to Vero cell monolayers in a 96-well plate format. At 24 (or 48) hours post-infection, we used a commercially available reagent to prepare cell lysates amenable to direct analysis by one-step SYBR Green quantitative reverse transcription PCR using primers specific for the RSV-N gene, thereby obviating the need for cumbersome RNA extraction and purification. The neutralization titer was defined as the reciprocal of the highest dilution needed to inhibit the PCR signal by 90% when compared with the mean value observed in virus control wells in the absence of neutralizing antibodies. RESULTS: We have developed a qPCR-based neutralization assay for human respiratory syncytial virus. Due to the sensitivity of qPCR in detecting virus replication, endpoints may be assessed as early as 24 hours post-infection. In addition, the dynamic range of qPCR provides a basis for the assay to be relatively robust to perturbations in input virus dose (i.e., the assay is in compliance with the Percentage Law). CONCLUSIONS: This qPCR-based neutralization assay is suitable for automated high-throughput applications. In addition, our experimental approach may be generalizable for the rapid development of neutralization assays for other virus families.

Immunogenicity, immunologic memory, and safety following measles revaccination in HIV-infected children receiving highly active antiretroviral therapy.

BACKGROUND: Response rates and immunologic memory following measles vaccination are reduced in human immunodeficiency virus (HIV)-infected children in the absence of highly active antiretroviral therapy (HAART). METHODS: HIV-infected children 2 to <19 years old receiving HAART and with HIV loads <30,000 copies/mL, CD4% ≥15, and ≥1 prior measles-mumps-rubella vaccination (MMR) were given another MMR. Measles antibody concentrations before and 8, 32, and 80 weeks postvaccination were determined by plaque reduction neutralization (PRN). A subset was given another MMR 4-5 years later, and PRN antibody was measured before and 7 and 28 days later. RESULTS: At entry, 52% of 193 subjects were seroprotected (PRN ≥120 mIU/mL). Seroprotection increased to 89% 8 weeks postvaccination, and remained at 80% 80 weeks postvaccination. Of 65 subjects revaccinated 4-5 years later, 85% demonstrated memory based on seroprotection before or 7 days after vaccination. HIV load ≤400 copies/mL at initial study vaccination was associated with higher seroprotection rates, greater antibody concentrations, and memory. Grade 3 fever or fatigue occurred in 2% of subjects. CONCLUSIONS: Measles revaccination induced high rates of seroprotection and memory in children receiving HAART. Both endpoints were associated with HIV viral load suppression. CLINICAL TRIALS REGISTRATION: NCT00013871 (www.clinicaltrials.gov).

Safety and immunogenicity of early measles vaccination in children born to HIV-infected mothers in the United States: results of Pediatric AIDS Clinical Trials Group (PACTG) protocol 225.

UNLABELLED: BACKGROUND.: ACTG (Pediatric AIDS Clinical Trials Group) 225, a multicenter, randomized, open-label trial in the United States evaluated reactogenicity and immunogenicity of 2 vaccination regimens: monovalent measles vaccine (Attenuvax) at 6 months of age and measles, mumps, and rubella, live attenuated (MMRII) vaccine at 12 months of age (2D), or only MMRII at 12 months of age (1D) in human immunodeficiency virus-infected (HIV-infected) (POS) and uninfected (NEG) children in the pre-highly active antiretroviral therapy (pre-HAART) period. METHODS: Plaque-reduction neutralization (PRN) of measles-neutralizing antibody titers were evaluated at study weeks 0, 6, 26, 32, 52, and 130 (∼3 years of age). RESULTS: The 110 subjects included: 65 2DNEG; 30 1DNEG; 7 2DPOS and 8 1DPOS. Vaccinations (n=175) were associated with no adverse experiences >Grade 2 except for Grade 3 fever (n=2, 1 1DPOS and 1 1DNEG). Six weeks after Attenuvax, all 2DPOS subjects (7/7) seroresponded (PRN titers ≥120 mIU/mL) with median titers significantly exceeding 2DNEG titers (2115 vs 628 mIU/mL, respectively; P=.023). At ∼3 years of age, 67% 1DPOS (4/6) and 83% 2DPOS (4/5) subjects maintained titers ≥120 mIU/mL. Prevaccination titers ≥25 mIU/mL among 2DNEG subjects correlated inversely with the likelihood of achieving titers ≥120 mIU/mL (56% vs 90%; P=.004). CONCLUSIONS: Among HIV-infected children pre-HAART, Attenuvax at 6 months was well tolerated and immunogenic. These data support the current World Health Organization (WHO) recommendation to administer a first dose of measles vaccine at 6 months of age to HIV-infected children.

Increasing the time of exposure to aerosol measles vaccine elicits an immune response equivalent to that seen in 9-month-old Mexican children given the same dose subcutaneously.

BACKGROUND: A 30-second aerosol measles vaccination successfully primes children 12 months of age and older but is poorly immunogenic when given to 9-month-old children. We examined the immune responses when increasing the duration to aerosol exposure in 9-month-olds. METHODS: One hundred and thirteen healthy 9-month-old children from Mexico City were enrolled; 58 received aerosol EZ measles vaccine for 2.5 minutes and 55 subcutaneously. Measles-specific neutralizing antibodies and cellular responses were measured before and at 3 and 6 months postimmunization. RESULTS: Adaptive immunity was induced in 97% after aerosol and 98% after subcutaneous administration. Seroconversion rates and GMCs were 95% and 373 mIU/mL (95% confidence interval [CI], 441-843) following aerosol vaccination and 91% and 306 mIU/mL (95% CI, 367-597) after subcutaneous administration at 3 months. The percentage of children with a measles-specific stimulation index ≥3 was 45% and 60% in the aerosol versus 55% and 59% in the subcutaneous group at 3 and 6 months, respectively. CD8 memory cell frequencies were higher in the aerosol group at 3 months compared with the subcutaneous group. Adverse reactions were comparable in both groups. CONCLUSIONS: Increasing exposure time to aerosol measles vaccine elicits immune responses that are comparable to those seen when an equivalent dose is administered by the subcutaneous route in 9-month-old infants.

Persistence of vaccine-induced measles antibody beyond age 12 months: a comparison of response to one and two doses of Edmonston-Zagreb measles vaccine among HIV-infected and uninfected children in Malawi.

BACKGROUND: Previously, we demonstrated that measles antibody prevalence was lower at age 12 months among children infected with human immunodeficiency virus (HIV) than uninfected children following measles vaccination (MV) at ages 6 and 9 months. Among HIV-uninfected children, measles antibody prevalence was lower among 1- than 2-dose MV recipients. Here, we report results through age 24 months. METHODS: Children born to HIV-infected mothers received MV at 6 and 9 months, and children of HIV-uninfected mothers were randomized to MV at 6 and 9 months or MV at 9 months. We followed children through age 24 months. The child's HIV status was determined and measles immunoglobulin G (IgG) level was measured by enzyme immunoassay (EIA) and by plaque reduction neutralization (PRN) on a subset. RESULTS: Among HIV-uninfected children, the difference in measles antibody prevalence at age 12 months between one- and two-dose recipients reported previously by EIA was shown to be smaller by PRN. By age 24 months, 84% and 87% of HIV-uninfected children receiving 1 or 2 doses, respectively, were seroprotected. Only 41% of 22 HIV-infected children were measles seroprotected at age 20 months. DISCUSSION: Measles seroprotection persisted through age 24 months among HIV-uninfected children who received 1 or 2 doses of MV. HIV-infected children demonstrated seroprotection through age 12 months, but this was not sustained.

Laboratory characterization of measles virus infection in previously vaccinated and unvaccinated individuals.

Waning immunity or secondary vaccine failure (SVF) has been anticipated by some as a challenge to global measles elimination efforts. Although such cases are infrequent, measles virus (MeV) infection can occur in vaccinated individuals following intense and/or prolonged exposure to an infected individual and may present as a modified illness that is unrecognizable as measles outside of the context of a measles outbreak. The immunoglobulin M response in previously vaccinated individuals may be nominal or fleeting, and viral replication may be limited. As global elimination proceeds, additional methods for confirming modified measles cases may be needed to understand whether SVF cases contribute to continued measles virus (MeV) transmission. In this report, we describe clinical symptoms and laboratory results for unvaccinated individuals with acute measles and individuals with SVF identified during MeV outbreaks. SVF cases were characterized by the serological parameters of high-avidity antibodies and distinctively high levels of neutralizing antibody. These parameters may represent useful biomarkers for classification of SVF cases that previously could not be confirmed as such using routine laboratory diagnostic techniques.

Summary of the Vaccines and Related Biological Products Advisory Committee meeting held to consider evaluation of vaccine candidates for the prevention of respiratory syncytial virus disease in RSV-naïve infants.

Respiratory syncytial virus (RSV), is a common cause of serious acute lower respiratory tract illness in infants and young children, causing substantial morbidity and mortality globally. Treatment is mainly supportive and currently there is no licensed preventive vaccine. Clinical trials conducted in the 1960s evaluating a formalin-inactivated RSV vaccine (FI-RSV) in RSV-naïve infants resulted in observations of enhanced respiratory disease (ERD) following subsequent natural RSV infection in vaccinees. In these studies, infants immunized with FI-RSV had higher rates of severe RSV disease compared with controls. This outcome redirected focus on identifying the immunologic mechanisms that precipitated ERD as a prerequisite to further vaccine development. Improved understanding of the immunopathogenesis of ERD derived from animal models has stimulated development of new candidate vaccines and engendered discussions among RSV experts about the safety data needed to advance these products into the clinic, and ultimately, into the target population of RSV-naïve infants. The recognition that multiple products would soon be ready for testing in infants and children prompted the FDA to hold a Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting to seek perspectives and advice of experts regarding the types and extent of preclinical and clinical data that might be needed to support testing in RSV-naïve infants for specific types of candidate RSV vaccines. Committee members agreed that, if certain conditions are met in preclinical and early clinical studies, it would be reasonable to move forward from studies in adults and older children and into clinical trials evaluating vaccine safety and efficacy in RSV-naïve infants. Herein, we review and summarize perspectives on the discussion regarding recommendations for RSV vaccine development in this population.

Measles Maternal Antibodies With Low Avidity Do Not Interfere With the Establishment of Robust Quantity and Quality Antibody Responses After the Primary Dose of Measles, Mumps, and Rubella Vaccine Administered at 12-Months of Age.

In this study, we illustrate, for the first time, that preexisting low-avidity neutralizing measles maternal antibodies do not interfere with the development of high concentrations of high-avidity measles antibodies in children immunized at age 12 months. This suggests that the quality of measles maternal antibodies, rather than the quantity, impacts immunogenicity of primary measles immunization.

Immunogenicity and safety of concurrent or sequential administration of live, attenuated SA 14-14-2 Japanese encephalitis vaccine (CD-JEV) and measles-mumps-rubella vaccine in infants 9-12 months of age in the Philippines: A non-inferiority Phase 4 randomized clinical trial.

INTRODUCTION: Japanese encephalitis (JE) virus is the leading cause of viral encephalitis across temperate and tropical zones of Asia. The live attenuated SA 14-14-2 JE vaccine (CD-JEV) is one of three vaccines prequalified by the World Health Organization (WHO) to prevent JE. When incorporating a new vaccine into a country's Expanded Program on Immunization (EPI), it is important to show that the new vaccine can be administered concurrently with other routine pediatric vaccines without impairing the immune responses or changing the safety profiles of the co-administered vaccines. This Phase 4 open-label study evaluated the safety and immunogenicity of measles-mumps-rubella (MMR) vaccine co-administered with CD-JEV. METHODS: The study randomized 628 healthy Filipino children aged between 9 and 10 months to receive MMR and CD-JEV concurrently or separately. MMR immunogenicity was measured 56 days after MMR vaccination using a measles plaque reduction neutralization test (PRNT), anti-mumps immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA), and anti-rubella IgG ELISA, respectively. Neutralizing antibody against JE virus was measured 28 days after CD-JEV vaccination using PRNT. Safety was assessed through solicitation of immediate reactions, adverse events (AEs) within 14 days of vaccination, unsolicited AEs occurring within 28 days, and serious adverse events (SAEs) during participation in the study. RESULTS/CONCLUSIONS: During the study, no post-vaccinal encephalitis cases or related SAEs were reported in either group. Concurrent immunization with CD-JEV and MMR vaccines was not associated with any unusual safety signals when compared with sequential immunization. No significant differences between the regimens were seen in seropositivity or serology titer/concentration results for any of the antigens. Co-administration of CD-JEV and MMR was non-inferior to single administration of either vaccine.

Development of a high-throughput assay to measure measles neutralizing antibodies.

Measles virus is highly infectious and remains a leading cause of vaccine preventable deaths in children. Neutralizing antibody responses elicited by measles virus infection or immunization are a serological correlate of protection. We describe a high-throughput neutralization assay to improve surveillance for measles immunity. Measles virus-antibody mixtures were incubated on Vero cell monolayers and 24 hours later cell-lysates harvested and subjected to one-step SYBR green RT-qPCR to amplify a target sequence within the measles virus nucleoprotein gene. Neutralization endpoint titers were interpolated to determine the dilution that inhibited the relative amplicon copy number by at least 90% compared to the mean signal obtained in virus control wells in the absence of serum. Anti-measles virus and anti-measles hemagglutinin antisera specifically neutralized measles virus in the microneutralization RT-qPCR assay while pre-immune sera and sera raised against other viruses did not. The microneutralization RT-qPCR assay obeyed the Percentage Law for measles virus inputs ranging from 100-5000 TCID50/well. The linear range of the assay corresponds to measles antibody concentrations of 30 to 3000 mIU/mL. Bland-Altman analysis and two-way analysis of variance demonstrated that results obtained using the microneutralization RT-qPCR assay were comparable to those obtained using a plaque reduction neutralization test and correctly identified human serum samples that were seropositive (95% and 100%, sensitivity and specificity, respectively). Furthermore, these comparisons suggest that a concentration of 300 mIU/mL may be a conservative cut-point to use to identify individuals likely to be protected against severe measles disease when the endpoint is based on 90% inhibition of virus replication. Measles virus microneutralization RT-qPCR is a rapid, sensitive, specific, and robust assay for detecting measles neutralizing antibodies that may help to improve immunization strategies nationally and achieve measles elimination globally.

Development of Luciferase Immunoprecipitation Systems (LIPS) Assay to Detect IgG Antibodies against Human Respiratory Syncytial Virus G-Glycoprotein.

Respiratory syncytial virus (RSV) causes severe lower respiratory tract disease in infants and the elderly. Although there is no licensed vaccine, RSV-F and -G glycoproteins are targets for vaccine development and therapeutics. We developed an assay that can detect anti-RSV-G IgG antibodies, either as a biomarker of natural exposure or immunization. RSV genes encoding native and mutated G (mG) proteins from subgroups A and B strains were cloned, expressed as luciferase-tagged proteins, and tested individually to detect anti-RSV-G specific IgG antibodies using a high-throughput luciferase immunoprecipitation system (LIPS-G). RSV monoclonal antibodies and polyclonal antisera specifically bound in the LIPS-GA and/or -GB assays; whereas anti-RSV-F and -N, and antisera against measles virus or human metapneumovirus did not bind. Anti-RSV-GA and -GB IgG responses detected in mice infected intranasally with RSV-A or -B strains were subtype specific. Subtype specific anti-RSV-GA or -GB IgG responses were also detected using paired serum samples from infants while human adolescent serum samples reacted in both LIPS-GA and -GB assays, reflecting a broader experience.

The effect of respiratory viruses on immunogenicity and protection induced by a candidate universal influenza vaccine in mice.

Current approaches to influenza control rely on vaccines matched to viruses in circulation. Universal influenza vaccines would offer the advantage of providing broad protection against diverse strains of influenza virus. Candidate universal vaccines are developed using model systems, often testing in naïve animals. Yet the human population is not naïve, having varied immune histories that include exposure to viruses. We studied a candidate universal influenza vaccine (replication deficient adenoviruses expressing the conserved influenza A antigens NP and M2 [A/NP+M2-rAd]) given intranasally, the route previously shown to be most effective. To model recipients exposed to viruses, we used mice given rhinovirus (RV1B), respiratory syncytial virus (RSV-A2), influenza B virus, or influenza A virus before or after universal influenza vaccine. Vaccine performance was assessed by measuring immune responses to NP and M2, and monitoring weight loss and survival following influenza A challenge. Prior influenza A virus infection enhanced the response to the vaccine by priming to conserved influenza A antigens. RSV-A2 or RV1B had no effect on antibody responses to NP and M2 in serum. None of the viruses inhibited the ability of the vaccine to protect against influenza A virus challenge. The study demonstrates that the usefulness of this universal vaccine is not confined to the immunologically naïve and supports possible use in a human population with a varied history of respiratory infections.

The influence of HIV-1 exposure and infection on levels of passively acquired antibodies to measles virus in Zambian infants.

BACKGROUND: The age at which passively acquired antibodies are lost is critical to determining the optimal age for measles vaccination. Little is known about the influence of human immunodeficiency virus type 1 (HIV-1) infection on levels of prevaccination antibodies to measles virus. METHODS: Antibodies to measles virus were measured by plaque reduction neutralization assay in HIV-1-infected, HIV-seropositive but uninfected, and HIV-seronegative Zambian infants aged 6 weeks to 9 months. Regression models were used to estimate age-specific antibody concentrations. RESULTS: Neutralizing antibodies to measles virus were measured in 652 plasma samples collected from 448 infants, of whom 61 (13.6%) were HIV-1 infected, 239 (53.4%) were HIV seropositive but uninfected, and 148 (33%) were HIV seronegative. The best fitting model suggests that HIV-1-infected infants have lower levels of passively acquired antibodies to measles virus at birth than do HIV-seronegative infants, but their antibody levels decrease more slowly. By 6 months of age, 91% (95% confidence interval, 83%-99%) of HIV-1-infected infants, 83% (95% confidence interval, 77%-89%) of HIV-seropositive but uninfected infants, and 58% (95% confidence interval, 51%-64%) of HIV-seronegative infants were estimated to have antibody levels that were unlikely to affect immune responses to measles vaccine (cutoff value for immune response, <50 mIU/mL). By 9 months of age, 99% of all infants had antibody levels <50 mIU/mL. CONCLUSIONS: Infants born to HIV-1-infected women are less likely to have passively acquired antibodies that would neutralize measles vaccine virus and, thus, have an increased risk of measles prior to the age of routine vaccination. Protection could be achieved by administration of the first dose of measles vaccine prior to 9 months of age.

Adverse Events After MMR or MMRV Vaccine in Infants Under Nine Months Old.

BACKGROUND: In the United States, measles is resurging, with more than 700 confirmed cases since January 2014. During measles outbreaks, vaccination as early as at 6 months of age is sometimes recommended for infants who are at risk for exposure. METHODS: We searched the Vaccine Adverse Event Reporting System for reports of measles, mumps and rubella vaccine combined or measles, mumps, rubella and varicella vaccine combined vaccination in children less than 9 months of age. We performed a clinical assessment of each report and summarized the frequency, range, onset time and severity of adverse events. RESULTS: After excluding 346 reports because they were duplicates or because they contained insufficient information about the child's age or vaccine(s), we retained 204 reports in the analysis, including 35 (17%) that were serious. Among the 169 nonserious reports, more than half (88; 52%) described a vaccination error without any adverse event per se. Other nonserious reports described fever, injection reactions and gastrointestinal symptoms. Serious adverse events included developmental disorders, fever and fussiness. There were 44 reports of fever, but only 4 cases began 5-12 days after immunization, the peak risk window. The vast majority of fever reports listed concomitant vaccines, such as diphtheria and tetanus toxoids, acellular or whole-cell pertussis vaccine. CONCLUSIONS: This review did not identify any major safety concerns. These findings may facilitate discussions about the risks and benefits of vaccinating infants who are potentially exposed to this life-threatening disease.

Challenges and opportunities in RSV vaccine development: Meeting report from FDA/NIH workshop.

Respiratory syncytial virus (RSV) is the most common cause of serious acute lower respiratory illness in infants and young children and a significant cause of disease burden in the elderly and immunocompromised. There are no licensed RSV vaccines to address this significant public health need. While advances in vaccine technologies have led to a recent resurgence in RSV vaccine development, the immune correlates of protection against RSV and the immunology of vaccine-associated enhanced respiratory disease (ERD) remain poorly understood. FDA's Center for Biologics Evaluation and Research (CBER) and NIH's National Institute of Allergy and Infectious Diseases (NIAID) organized and co-sponsored an RSV Vaccines Workshop in Bethesda, Maryland on June 1 and 2, 2015. The goal of the conference was to convene scientists, regulators, and industry stakeholders to discuss approaches to RSV vaccine development within the context of three target populations - infants and children, pregnant women, and individuals >60years of age. The agenda included topics related to RSV vaccine development in general, as well as considerations specific to each target population, such as clinical and serological endpoints. The meeting focused on vaccine development for high income countries (HIC), because issues relevant to vaccine development for low and middle income countries (LMIC) have been discussed in other forums. This manuscript summarizes the discussion of clinical, scientific, and regulatory perspectives, research gaps, and lessons learned.