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Background. Antibody titers to influenza hemagglutinin (HA) and neuraminidase (NA) surface antigens increase in the weeks after infection or vaccination, and decrease over time thereafter. However, the rate of decline has been debated. Methods. Healthy adults participating in a randomized placebo-controlled trial of inactivated (IIV) and liveattenuated (LAIV) influenza vaccines provided blood specimens immediately prior to vaccination and at 1, 6, 12, and 18 months postvaccination. Approximately half had also been vaccinated in the prior year. Rates of hemagglutination inhibition (HAI) and neuraminidase inhibition (NAI) titer decline in the absence of infection were estimated. Results. HAI and NAI titers decreased slowly over 18 months; overall, a 2-fold decrease in antibody titer was estimated to take > 600 days for all HA and NA targets. Rates of decline were fastest among IIV recipients, explained in part by faster declines with higher peak postvaccination titer. IIV and LAIV recipients vaccinated 2 consecutive years exhibited significantly lower HAI titers following vaccination in the second year, but rates of persistence were similar. Conclusions. Antibody titers to influenza HA and NA antigens may persist over multiple seasons; however, antigenic drift of circulating viruses may still necessitate annual vaccination. Vaccine seroresponse may be impaired with repeated vaccination.

While influenza virus diversity and antigenic drift have been well characterized on a global scale, the factors that influence the virus' rapid evolution within and between human hosts are less clear. Given the modest effectiveness of seasonal vaccination, vaccine-induced antibody responses could serve as a potent selective pressure for novel influenza variants at the individual or community level. We used next generation sequencing of patient-derived viruses from a randomized, placebo-controlled trial of vaccine efficacy to characterize the diversity of influenza A virus and to define the impact of vaccine-induced immunity on within-host populations. Importantly, this study design allowed us to isolate the impact of vaccination while still studying natural infection. We used pre-season hemagglutination inhibition and neuraminidase inhibition titers to quantify vaccine-induced immunity directly and to assess its impact on intrahost populations. We identified 166 cases of H3N2 influenza over 3 seasons and 5119 person-years. We obtained whole genome sequence data for 119 samples and used a stringent and empirically validated analysis pipeline to identify intrahost single nucleotide variants at ≥1% frequency. Phylogenetic analysis of consensus hemagglutinin and neuraminidase sequences showed no stratification by pre-season HAI and NAI titer, respectively. In our study population, we found that the vast majority of intrahost single nucleotide variants were rare and that very few were found in more than one individual. Most samples had fewer than 15 single nucleotide variants across the entire genome, and the level of diversity did not significantly vary with day of sampling, vaccination status, or pre-season antibody titer. Contrary to what has been suggested in experimental systems, our data indicate that seasonal influenza vaccination has little impact on intrahost diversity in natural infection and that vaccine-induced immunity may be only a minor contributor to antigenic drift at local scales.

The role of viral interaction—where one virus enhances or inhibits infection with another virus—in respiratory virus transmission is not well characterized. This study used data from 4029 total participants from 957 households who participated in a prospective household cohort study in Southeast Michigan, U.S.A to examine how viral coinfection and cocirculation may impact transmission of symptomatic influenza and respiratory syncytial virus infections. We utilized multivariable mixed effects regression to estimate transmission risk when index cases were coinfected with multiple viruses and when viruses cocirculated within households. This analysis included 201 coinfections involving influenza A virus, 67 involving influenza B virus, and 181 involving respiratory syncytial virus. We show that exposure to symptomatic coinfected index cases was associated with reduced risk of influenza A virus and respiratory syncytial virus transmission compared to exposure to singly infected cases, while infection with another virus was associated with increased risk of acquisition of these viruses. Exposure to coinfected cases among contacts infected with other viruses was associated with increased risk of influenza B virus acquisition. These results suggest that viral interaction may impact symptomatic transmission of these viruses. Interactions between respiratory viruses in co-infections may impact their transmission dynamics but impacts at the individual-level are not well understood. Here, the authors use data from a prospective household-based cohort study to investigate the impact of co-infection on transmission and acquisition of influenza and RSV.

Data are scarce regarding the comparative efficacies of the inactivated (intramuscular administration) and live attenuated (intranasal administration) seasonal influenza vaccines. During the 2007–2008 influenza season, 1952 healthy young adults were enrolled in a randomized, double-blind, placebo-controlled study of these two vaccines. The inactivated vaccine was found to have an absolute efficacy of 68%, whereas the live attenuated vaccine had an absolute efficacy of 36%. The inactivated (intramuscular administration) vaccine was found to have an absolute efficacy of 68%, whereas the live attenuated (intranasal administration) vaccine had an absolute efficacy of 36%. Two different types of vaccine for the prevention of seasonal influenza are currently licensed, one containing inactivated viruses and the other containing live attenuated viruses. Both vaccines are trivalent, with the three components updated annually as needed on the basis of national and international recommendations. 1 The efficacy of both vaccines can be affected by a number of factors, including the age and health of the vaccine recipients, and by the extent of antigenic similarity between the strains included in the vaccines and those that actually circulate months later. 2 – 6 Thus, there can be differences in efficacy from year to year. . . .

Households play a major role in community spread of influenza and are potential targets for mitigation strategies. We enrolled and followed 328 households with children during the 2010-2011 influenza season; this season was characterized by circulation of influenza A (H3N2), A (H1N1)pdm09 and type B viruses. Specimens were collected from subjects with acute respiratory illnesses and tested for influenza in real-time reverse transcriptase polymerase chain reaction (RT-PCR) assays. Influenza cases were classified as community-acquired or household-acquired, and transmission parameters estimated. Influenza was introduced to 78 (24%) households and transmission to exposed household members was documented in 23 households. Transmission was more likely in younger households (mean age <22 years) and those not reporting home humidification, but was not associated with household vaccination coverage. The secondary infection risk (overall 9.7%) was highest among young children (<9 years) and varied substantially by influenza type/subtype with the highest risk for influenza A (H3N2). The serial interval (overall 3.2 days) also varied by influenza type and was longest for influenza B. Duration of symptomatic illness was shorter in children compared with adults, and did not differ by influenza vaccination status. Prospective study of households with children over a single influenza season identified differences in household transmission by influenza type/subtype, subject age, and home humidification, suggesting possible targets for interventions to reduce transmission.

•Serum collected at hospital admission can be used to assess influenza protection.•There was no trend in antibody among influenza cases by day of collection (0–10).•Inpatients who received influenza vaccination had more antibody than unvaccinated.•Associations between antibody and infection paralleled vaccine effectiveness. Influenza vaccines are important for prevention of influenza-associated hospitalization. However, the effectiveness of influenza vaccines can vary by year and influenza type and subtype and mechanisms underlying this variation are incompletely understood. Assessments of serologic correlates of protection can support interpretation of influenza vaccine effectiveness in hospitalized populations. We enrolled adults hospitalized for treatment of acute respiratory illnesses during the 2014–2015 and 2015–2016 influenza seasons whose symptoms began <10 days prior to enrollment. Influenza infection status was determined by RT-PCR. Influenza vaccination status was defined by self-report and medical record/registry documentation. Serum specimens collected at hospital admission were tested in hemagglutination-inhibition (HAI) and neuraminidase-inhibition (NAI) assays. We evaluated how well antibody measured in these specimens represented pre-infection immune status, and measured associations between antibody and influenza vaccination and infection. Serum specimens were retrieved for 315 participants enrolled during the 2014–2015 season and 339 participants during the 2015–2016 season. Specimens were collected within 3 days of illness onset from 65% of participants. Geometric mean titers (GMTs) did not vary by the number of days from illness onset to specimen collection among influenza positive participants suggesting that measured antibody was representative of pre-infection immune status rather than a de novo response to infection. In both seasons, vaccinated participants had higher HAI and NAI GMTs than unvaccinated. HAI titers against the 2014–2015 A(H3N2) vaccine strain did not correlate with protection from infection with antigenically-drifted A(H3N2) viruses that circulated that season. In contrast, higher HAI titers against the A(H1N1)pdm09 vaccine strain were associated with reduced odds of A(H1N1)pdm09 infection in 2015–2016. Serum collected shortly after illness onset at hospital admission can be used to assess correlates of protection against influenza infection. Broader implementation of similar studies would provide an opportunity to understand the successes and shortcomings of current influenza vaccines.

Background. Laboratory correlates of influenza vaccine protection can best be identified by examining people who are infected despite vaccination. While the importance of antibody to viral hemagglutinin (HA) has long been recognized, the level of protection contributed independently by antibody to viral neuraminidase (NA) has not been determined. Methods. Sera from a controlled trial of the efficacies of inactivated influenza vaccine (IIV) and live attenuated influenza vaccine (LAIV) were tested by hemagglutination inhibition (HAI) assay, microneutralization (MN) assay, and a newly standardized lectin-based neuraminidase inhibition (NAI) assay. Results. The NAI assay detected a vaccine response in 37% of IIV recipients, compared with 77% and 67% of participants in whom responses were detected by the HAI and MN assays, respectively. For LAIV recipients, the NAI, HAI, and MN assays detected responses in 6%, 21%, and 17%, respectively. In IIV recipients, as NAI assay titers rose, the frequency of infection fell, similar to patterns seen with HAI and MN assays. HAI and MN assay titers were highly correlated, but NAI assay titers exhibited less of a correlation. Analyses suggested an independent role for NAI antibody in protection, which was similar in the IIV, LAIV, and placebo groups. Conclusions. While NAI antibody is not produced to a large extent in response to current IIV, it appears to have an independent role in protection. As new influenza vaccines are developed, NA content should be considered. Clinical Trials Registration. NCT00538512.

Background. Antibody to influenza virus hemagglutinin has been traditionally associated with protection. Questions have been raised about its use as a surrogate for vaccine efficacy, particularly with regard to an absolute titer indicating seroprotection. Methods. We examined hemagglutination-inhibition (HAI) antibody titers in subjects from a placebo-controlled trial of inactivated and live attenuated vaccines and compared titers in subjects with symptomatic influenza (cases) to those without influenza infection (noncases). Results. Prevaccination and postvaccination geometric mean titers were both significantly lower for cases compared with noncases in all intervention groups. Frequency of postvaccination seroconversion did not significantly differ for cases and noncases in either vaccine group. Among live attenuated vaccine and placebo recipients, cases were less likely than noncases to have postvaccination HAI titers ≥32 or 64. Nearly all recipients of inactivated vaccine had postvaccination titers of at least 64, and the small number of vaccine failures were scattered across titers ranging from 64 to 2048. Conclusions. While HAI antibody is the major correlate of protection, postvaccination titers alone should not be used as a surrogate for vaccine efficacy. Vaccine failures from clinical trials need to be examined to determine why seemingly protective HAI titers may not protect.

Abstract Background In recent influenza seasons, the effectiveness of inactivated influenza vaccines against circulating A(H3N2) virus has been lower than against A(H1N1)pdm09 and B viruses, even when circulating viruses remained antigenically similar to vaccine components. Methods During the 2016–2017 influenza season, vaccine effectiveness (VE) across age groups and vaccine types was examined among outpatients with acute respiratory illness at 5 US sites using a test-negative design that compared the odds of vaccination among reverse transcription polymerase chain reaction–confirmed influenza positives and negatives. Results Among 7083 enrollees, 1342 (19%) tested positive for influenza A(H3N2), 648 (9%) were positive for influenza B (including B/Yamagata, n = 577), and 5040 (71%) were influenza negative. Vaccine effectiveness was 40% (95% confidence interval [CI], 32% to 46%) against any influenza virus, 33% (95% CI, 23% to 41%) against influenza A(H3N2) viruses, and 53% (95% CI, 43% to 61%) against influenza B viruses. Conclusions The 2016–2017 influenza vaccines provided moderate protection against any influenza among outpatients but were less protective against influenza A(H3N2) viruses than B viruses. Approaches to improving effectiveness against A(H3N2) viruses are needed. The 2016–2017 influenza vaccines provided moderate protection against any influenza among outpatients but were less protective against influenza A(H3N2) viruses than B viruses.

Abstract Background Evidence establishing effectiveness of influenza vaccination for prevention of severe illness is limited. The US Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN) is a multiyear test-negative case-control study initiated in 2015–2016 to estimate effectiveness of vaccine in preventing influenza hospitalization among adults. Methods Adults aged ≥18 years admitted to 8 US hospitals with acute respiratory illness and testing positive for influenza by polymerase chain reaction were cases; those testing negative were controls. Vaccine effectiveness was estimated with logistic regression adjusting for age, comorbidities, and other confounding factors and stratified by frailty, 2-year vaccination history, and clinical presentation. Results We analyzed data from 236 cases and 1231 controls; mean age was 58 years. More than 90% of patients had ≥1 comorbidity elevating risk of influenza complications. Fifty percent of cases and 70% of controls were vaccinated. Vaccination was 51% (95% confidence interval [CI], 29%–65%) and 53% (95% CI, 11%–76%) effective in preventing hospitalization due to influenza A(H1N1)pdm09 and influenza B virus infection, respectively. Vaccine was protective for all age groups. Conclusions During the 2015–2016 US influenza A(H1N1)pdm09–predominant season, we found that vaccination halved the risk of influenza-association hospitalization among adults, most of whom were at increased risk of serious influenza complications due to comorbidity or age. During the 2015–2016 US influenza A(H1N1)pdm09–predominant season, we found that vaccination halved the risk of influenza-association hospitalization among adults, most of whom were at increased risk of serious influenza complications due to comorbidity or age.