Despite the major burden of seasonal influenza, only the threat of pandemics is of universal concern globally. Past pandemics are reviewed, identifying measures that will be of value going forward. ...These will also help in controlling seasonal influenza.
Abstract
Seasonal influenza is an annual occurrence, but it is the threat of pandemics that produces universal concern. Recurring reports of avian influenza viruses severely affecting humans have served as constant reminders of the potential for another pandemic. Review of features of the 1918 influenza pandemic and subsequent ones helps in identifying areas where attention in planning is critical. Key among such issues are likely risk groups and which interventions to employ. Past pandemics have repeatedly underscored, for example, the vulnerability of groups such as pregnant women and taught other lessons valuable for future preparedness. While a fundamental difficulty in planning for the next pandemic remains their unpredictability and infrequency, this uncertainty can be mitigated, in part, by optimizing the handling of the much more predictable occurrence of seasonal influenza. Improvements in antivirals and novel vaccine formulations are critical in lessening the impact of both pandemic and seasonal influenza.
Summary Background Despite widespread use, questions remain about the efficacy of oseltamivir in the treatment of influenza. We aimed to do an individual patient data meta-analysis for all clinical ...trials comparing oseltamivir with placebo for treatment of seasonal influenza in adults regarding symptom alleviation, complications, and safety. Methods We included all published and unpublished Roche-sponsored randomised placebo-controlled, double-blind trials of 75 mg twice a day oseltamivir in adults. Trials of oseltamivir for treatment of naturally occurring influenza-like illness in adults reporting at least one of the study outcomes were eligible. We also searched Medline, PubMed, Embase, the Cochrane Central Register of Controlled Trials, and the ClinicalTrials.gov trials register for other relevant trials published before Jan 1, 2014 (search last updated on Nov 27, 2014). We analysed intention-to-treat infected, intention-to-treat, and safety populations. The primary outcome was time to alleviation of all symptoms analysed with accelerated failure time methods. We used risk ratios and Mantel-Haenszel methods to work out complications, admittances to hospital, and safety outcomes. Findings We included data from nine trials including 4328 patients. In the intention-to-treat infected population, we noted a 21% shorter time to alleviation of all symptoms for oseltamivir versus placebo recipients (time ratio 0·79, 95% CI 0·74–0·85; p<0·0001). The median times to alleviation were 97·5 h for oseltamivir and 122·7 h for placebo groups (difference −25·2 h, 95% CI −36·2 to −16·0). For the intention-to-treat population, the estimated treatment effect was attenuated (time ratio 0·85) but remained highly significant (median difference −17·8 h). In the intention-to-treat infected population, we noted fewer lower respiratory tract complications requiring antibiotics more than 48 h after randomisation (risk ratio RR 0·56, 95% CI 0·42–0·75; p=0·0001; 4·9% oseltamivir vs 8·7% placebo, risk difference −3·8%, 95% CI −5·0 to −2·2) and also fewer admittances to hospital for any cause (RR 0·37, 95% CI 0·17–0·81; p=0·013; 0·6% oseltamivir, 1·7% placebo, risk difference −1·1%, 95% CI −1·4 to −0·3). Regarding safety, oseltamivir increased the risk of nausea (RR 1·60, 95% CI 1·29–1·99; p<0·0001; 9·9% oseltamivir vs 6·2% placebo, risk difference 3·7%, 95% CI 1·8–6·1) and vomiting (RR 2·43, 95% CI 1·83–3·23; p<0·0001; 8·0% oseltamivir vs 3·3% placebo, risk difference 4·7%, 95% CI 2·7–7·3). We recorded no effect on neurological or psychiatric disorders or serious adverse events. Interpretation Our findings show that oseltamivir in adults with influenza accelerates time to clinical symptom alleviation, reduces risk of lower respiratory tract complications, and admittance to hospital, but increases the occurrence of nausea and vomiting. Funding Multiparty Group for Advice on Science (MUGAS) foundation.
Abstract
For 50 years it has been known that antibodies to neuraminidase (NA) protect against infection during seasonal and pandemic influenza outbreaks. However, NA is largely ignored in the ...formulation and standardization of our current influenza vaccines. There are a number of factors that contributed to this antigen being forgotten, including the lack of an easily performed test to measure NA antibody. With the availability of that test, it has been possible to show its independent contribution to protection in various situations. The challenge now is to make it possible to include known amounts of NA in investigational vaccines or to routinely measure NA content in licensed vaccines. Vaccines containing optimal amounts of NA may be particularly useful when there are antigenic changes, either drift or shift, in the hemagglutinin because NA immunity offers broad protection. It is now time to remember the NA as we work toward improved influenza vaccines.
The term "original antigenic sin" was coined approximately 60 years ago to describe the imprinting by the initial first influenza A virus infection on the antibody response to subsequent vaccination. ...These studies did not suggest a reduction in the response to current antigens but instead suggested anamnestic recall of antibody to earlier influenza virus strains. Then, approximately 40 years ago, it was observed that sequential influenza vaccination might lead to reduced vaccine effectiveness (VE). This conclusion was largely dismissed after an experimental study involving sequential administration of then-standard influenza vaccines. Recent observations have provided convincing evidence that reduced VE after sequential influenza vaccination is a real phenomenon. We propose that such reduction in VE be termed "negative antigenic interaction," given that there is no age cohort effect. In contrast, the potentially positive protective effect of early influenza virus infection later in life continues to be observed. It is essential that we understand better the immunologic factors underlying both original antigenic sin and negative antigenic interaction, to support development of improved influenza vaccines and vaccination strategies.
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.
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