Biology subjects

Monto, A. S.

Publications and source records attributed to Monto, A. S..

5 recordsLinked to original sources

bioRxiv2018

Antibodies against egg- and cell-grown influenza A(H3N2) viruses in adults hospitalized during the 2017-2018 season

BackgroundThe 2017-2018 US influenza season was severe with low vaccine effectiveness. Circulating A(H3N2) viruses from multiple genetic groups were antigenically similar to cell-grown vaccine strains. However, most influenza vaccines are egg-propagated.\n\nMethodsSerum was collected shortly after illness onset from 15 PCR confirmed A(H3N2) infected cases and 15 uninfected (controls) hospitalized adults enrolled in an influenza vaccine effectiveness study.\n\nGeometric mean titers against egg- and cell-grown A/Hong Kong/4801/2014 A(H3N2) vaccine strains and representative circulating viruses (including A/Washington/16/2017) were determined by microneutralization (MN) assays. Independent effects of strain-specific titers on susceptibility were estimated by logistic regression.\n\nResultsMN titers against egg-A/Hong Kong were significantly higher among those who were vaccinated (MN GMT: 173 vs 41; P = 0.01). However, antibody titers to cell-grown viruses were much lower in all individuals (P>0.05) regardless of vaccination. In unadjusted models, a 2-fold increase in MN titers against egg-A/Hong Kong was not significantly protective against infection (29% reduction; p=0.09), but a similar increase in cell-A/Washington titer (3C.2a2) was protective (60% reduction; p=0.02). A similar increase in egg-A/Hong Kong titer was not significantly associated with odds of infection when adjusting for MN titers against A/Washington (15% reduction; P=0.61). A 54% reduction of odds of infection was observed with a 2-fold increase in A/Washington (not significant; P=0.07), adjusted for egg-A/Hong Kong titer.\n\nConclusionAlthough individuals vaccinated in 2017-2018 had high antibody titers against the egg-adapted vaccine strain, antibody responses to cell-grown circulating viruses may not be sufficient to provide protection, likely due to egg-adaptation in the vaccine.

epidemiology↗

bioRxiv2018

Evaluation of correlates of protection against influenza A(H3N2) and A(H1N1)pdm09 infection: Applications to the hospitalized patient population.

BackgroundInfluenza vaccines are important for prevention of influenza-associated hospitalization. Assessments of serologic correlates of protection can support interpretation of influenza vaccine effectiveness evaluations in hospitalized populations.\n\nMethodsSerum specimens collected at admission from adults hospitalized for treatment of acute respiratory illnesses during two influenza seasons were tested in hemagglutination-inhibition (HAI) and neuraminidase-inhibition (NAI) assays. We evaluated the suitability of these specimens as proxies for pre-infection immune status, and measured associations between antibody titers and influenza vaccination and infection\n\nResultsSpecimens were collected within 3 days of illness onset from 65% of participants; geometric mean titers (GMTs) did not vary by day of collection. In both seasons, vaccinated participants had higher HAI and NAI GMTs than unvaccinated participants. 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.\n\nConclusionsSerum collected after 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.

epidemiology↗

bioRxiv2018

Identification of human vaccinees that possess antibodies targeting the egg-adapted hemagglutinin receptor binding site of an H1N1 influenza vaccine strain

Human influenza viruses passaged in eggs often acquire mutations in the hemagglutinin (HA) receptor binding site (RBS). To determine if egg-adapted H1N1 vaccines commonly elicit antibodies targeting the egg-adapted RBS of HA, we completed hemagglutinin-inhibition assays with A/California/7/2009 HA and egg-adapted A/California/7/2009-X-179A HA using sera collected from 159 humans vaccinated with seasonal influenza vaccines during the 2015-16 season. We found that ~5% of participants had [≥]4-fold higher antibody titers to the egg-adapted viral strain compared to wild type viral strain. We used reverse-genetics to demonstrate that a single egg-adapted HA RBS mutation (Q226R) was responsible for this phenotype.

microbiology↗

bioRxiv2017

The evolutionary dynamics of influenza A virus within and between human hosts

The global evolutionary dynamics of influenza virus ultimately derive from processes that take place within and between infected individuals. Here we define the dynamics of influenza A virus populations in human hosts through next generation sequencing of 249 specimens from 200 individuals collected over 6290 person-seasons of observation. Because these viruses were collected over 5 seasons from individuals in a prospective community-based cohort, they are broadly representative of natural human infections with seasonal viruses. We used viral sequence data from 35 serially sampled individuals to estimate a within host effective population size of 30-70 and an in vivo mutation rate of 4x10-5 per nucleotide per cellular infectious cycle. These estimates are consistent across several models and robust to the models' underlying assumptions. We also identified 43 epidemiologically linked and genetically validated transmission pairs. Maximum likelihood optimization of multiple transmission models estimates an effective transmission bottleneck of 1-2 distinct genomes. Our data suggest that positive selection of novel viral variants is inefficient at the level of the individual host and that genetic drift and other stochastic processes dominate the within and between host evolution of influenza A viruses.

microbiology↗

bioRxiv2016

Vaccination has minimal impact on the intrahost diversity of H3N2 influenza viruses

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.

microbiology↗