Suzanne E. Ohmit

Influenza Viruses Resistant to the Antiviral Drug Oseltamivir: Transmission Studies in Ferrets

Three type A influenza viruses, each of which has a distinct neuraminidase-gene mutation and is resistant to the neuraminidase inhibitor oseltamivir, have been isolated. Previously, in the ferret model, an R292K mutant of a type A (H3N2) virus was not transmitted under conditions in which the wild-type virus was transmitted. This model was used to investigate whether the E119V mutant of a type A (H3N2) virus and the H274Y mutant of a type A (H1N1) virus would be transmitted under similar circumstances. Both mutant viruses were transmitted, although the H274Y mutant required a 100-fold-higher dose for infection of donor ferrets and was transmitted more slowly than was the wild type. Both the mutant and the wild-type viruses retained their genotypic characteristics.

Comparative Efficacy of Inactivated and Live Attenuated Influenza Vaccines

BACKGROUNDnThe efficacy of influenza vaccines may vary from year to year, depending on a variety of factors, and may differ for inactivated and live attenuated vaccines.nnnMETHODSnWe carried out a randomized, double-blind, placebo-controlled trial of licensed inactivated and live attenuated influenza vaccines in healthy adults during the 2007-2008 influenza season and estimated the absolute and relative efficacies of the two vaccines.nnnRESULTSnA total of 1952 subjects were enrolled and received study vaccines in the fall of 2007. Influenza activity occurred from January through April 2008, with the circulation of influenza types A (H3N2) (about 90%) and B (about 9%). Absolute efficacy against both types of influenza, as measured by isolating the virus in culture, identifying it on real-time polymerase-chain-reaction assay, or both, was 68% (95% confidence interval [CI], 46 to 81) for the inactivated vaccine and 36% (95% CI, 0 to 59) for the live attenuated vaccine. In terms of relative efficacy, there was a 50% (95% CI, 20 to 69) reduction in laboratory-confirmed influenza among subjects who received inactivated vaccine as compared with those given live attenuated vaccine. The absolute efficacy against the influenza A virus was 72% (95% CI, 49 to 84) for the inactivated vaccine and 29% (95% CI, -14 to 55) for the live attenuated vaccine, with a relative efficacy of 60% (95% CI, 33 to 77) for the inactivated vaccine.nnnCONCLUSIONSnIn the 2007-2008 season, the inactivated vaccine was efficacious in preventing laboratory-confirmed symptomatic influenza A (predominately H3N2) in healthy adults. The live attenuated vaccine also prevented influenza illnesses but was less efficacious. (ClinicalTrials.gov number, NCT00538512.)

Influenza vaccine effectiveness in the 2011-2012 season: protection against each circulating virus and the effect of prior vaccination on estimates

BACKGROUNDnEach year, the US Influenza Vaccine Effectiveness Network examines the effectiveness of influenza vaccines in preventing medically attended acute respiratory illnesses caused by influenza.nnnMETHODSnPatients with acute respiratory illnesses of ≤ 7 days duration were enrolled at ambulatory care facilities in 5 communities. Specimens were collected and tested for influenza by real-time reverse-transcriptase polymerase chain reaction. Receipt of influenza vaccine was defined based on documented evidence of vaccination in medical records or immunization registries. Vaccine effectiveness was estimated in adjusted logistic regression models by comparing the vaccination coverage in those who tested positive for influenza with those who tested negative.nnnRESULTSnThe 2011-2012 season was mild and peaked late, with circulation of both type A viruses and both lineages of type B. Overall adjusted vaccine effectiveness was 47% (95% confidence interval [CI], 36-56) in preventing medically attended influenza; vaccine effectiveness was 65% (95% CI, 44-79) against type A (H1N1) pdm09 but only 39% (95% CI, 23-52) against type A (H3N2). Estimates of vaccine effectiveness against both type B lineages were similar (overall, 58%; 95% CI, 35-73). An apparent negative effect of prior year vaccination on current year effectiveness estimates was noted, particularly for A (H3N2) outcomes.nnnCONCLUSIONSnVaccine effectiveness in the 2011-2012 season was modest overall, with lower effectiveness against the predominant A (H3N2) virus. This may be related to antigenic drift, but past history of vaccination might also play a role.

Influenza Vaccine Effectiveness in the United States During 2012–2013: Variable Protection by Age and Virus Type

Background.u2003During the 2012–2013 influenza season, there was cocirculation of influenza A(H3N2) and 2 influenza B lineage viruses in the United States. Methods.u2003Patients with acute cough illness for ≤7 days were prospectively enrolled and had swab samples obtained at outpatient clinics in 5 states. Influenza vaccination dates were confirmed by medical records. The vaccine effectiveness (VE) was estimated as [100% × (1 − adjusted odds ratio)] for vaccination in cases versus test-negative controls. Results.u2003Influenza was detected in 2307 of 6452 patients (36%); 1292 (56%) had influenza A(H3N2), 582 (25%) had influenza B/Yamagata, and 303 (13%) had influenza B/Victoria. VE was 49% (95% confidence interval [CI], 43%–55%) overall, 39% (95% CI, 29%–47%) against influenza A(H3N2), 66% (95% CI, 58%–73%) against influenza B/Yamagata (vaccine lineage), and 51% (95% CI, 36%–63%) against influenza B/Victoria. VE against influenza A(H3N2) was highest among persons aged 50–64 years (52%; 95% CI, 33%–65%) and persons aged 6 months–8 years (51%; 95% CI, 32%–64%) and lowest among persons aged ≥65 years (11%; 95% CI, −41% to 43%). In younger age groups, there was evidence of residual protection from receipt of the 2011–2012 vaccine 1 year earlier. Conclusions.u2003The 2012–2013 vaccines were moderately effective in most age groups. Cross-lineage protection and residual effects from prior vaccination were observed and warrant further investigation.

Influenza Vaccine Effectiveness in the Community and the Household

BACKGROUNDnThere is a recognized need to determine influenza vaccine effectiveness on an annual basis and a long history of studying respiratory illnesses in households.nnnMETHODSnWe recruited 328 households with 1441 members, including 839 children, and followed them during the 2010-2011 influenza season. Specimens were collected from subjects with reported acute respiratory illnesses and tested by real-time reverse transcriptase polymerase chain reaction. Receipt of influenza vaccine was defined based on documented evidence of vaccination in medical records or an immunization registry. The effectiveness of 2010-2011 influenza vaccination in preventing laboratory-confirmed influenza was estimated using Cox proportional hazards models adjusted for age and presence of high-risk condition, and stratified by prior season (2009-2010) vaccination status.nnnRESULTSnInfluenza was identified in 78 (24%) households and 125 (9%) individuals; the infection risk was 8.5% in the vaccinated and 8.9% in the unvaccinated (P = .83). Adjusted vaccine effectiveness in preventing community-acquired influenza was 31% (95% confidence interval [CI], -7% to 55%). In vaccinated subjects with no evidence of prior season vaccination, significant protection (62% [95% CI, 17%-82%]) against community-acquired influenza was demonstrated. Substantially lower effectiveness was noted among subjects who were vaccinated in both the current and prior season. There was no evidence that vaccination prevented household transmission once influenza was introduced; adults were at particular risk despite vaccination.nnnCONCLUSIONSnVaccine effectiveness estimates were lower than those demonstrated in other observational studies carried out during the same season. The unexpected findings of lower effectiveness with repeated vaccination and no protection given household exposure require further study.

Prevention of Symptomatic Seasonal Influenza in 2005–2006 by Inactivated and Live Attenuated Vaccines

BACKGROUNDnThe efficacy of influenza vaccines may vary annually. In 2004-2005, when antigenically drifted viruses were circulating, a randomized, placebo-controlled trial involving healthy adults showed that inactivated vaccine appeared to be efficacious, whereas live attenuated vaccine appeared to be less so.nnnMETHODSnIn 2005-2006, we continued our trial, examining the absolute and relative efficacies of the live attenuated and inactivated vaccines in preventing laboratory-confirmed symptomatic influenza.nnnRESULTSnA total of 2058 persons were vaccinated in October and November 2005. Studywide influenza activity was prolonged but of low intensity; type A (H3N2) virus was circulating, which was antigenically similar to the vaccine strain. The absolute efficacy of the inactivated vaccine was 16% (95% confidence interval [CI], -171% to 70%) for the virus identification end point (virus isolation in cell culture or identification through polymerase chain reaction) and 54% (95% CI, 4%-77%) for the primary end point (virus isolation or increase in serum antibody titer). The absolute efficacies of the live attenuated vaccine for these end points were 8% (95% CI, -194% to 67%) and 43% (95% CI, -15% to 71%), respectively.nnnCONCLUSIONSnWith serologic end points included, efficacy was demonstrated for the inactivated vaccine in a year with low influenza attack rates. The efficacy of the live attenuated vaccine was slightly less than that of the inactivated vaccine, but not statistically greater than that of the placebo.

Efficacy Studies of Influenza Vaccines: Effect of End Points Used and Characteristics of Vaccine Failures

BACKGROUNDnEnd points used to detect influenza in vaccine efficacy trials have varied. Both the inactivated and live attenuated influenza vaccines are efficacious; however, failure to protect occurs.nnnMETHODSnWe compared characteristics of influenza A (H3N2) and B cases from 3 years of a comparative placebo-controlled trial of inactivated and live attenuated vaccines, and we evaluated the laboratory end points used to determine efficacy.nnnRESULTSnAlthough illness duration and reported symptoms did not differ by intervention, subjects with influenza in the inactivated vaccine group were less likely than those in the placebo group to report medically attended illnesses. All influenza type A (H3N2) and B cases isolated in cell culture were also identified by real-time polymerase chain reaction (rtPCR). However, only 69% of type A (H3N2) cases identified by rtPCR also were isolated in cell culture. Isolation frequency was lowest among live attenuated vaccine failures, a reflection of lower specimen viral loads. Among cases of rtPCR identified influenza A (H3N2), 90% of placebo and 87% of live attenuated vaccine recipients but only 23% of inactivated vaccine recipients demonstrated serologic confirmation of infection.nnnCONCLUSIONSnIn influenza vaccine efficacy studies, virus identification using rtPCR is the ideal end point. Isolation in cell culture will miss cases, and a serologic end point alone will overestimate inactivated vaccine efficacy.

Mucosal Candidal Colonization and Candidiasis in Women with or at Risk for Human Immunodeficiency Virus Infection

The epidemiology of mucosal candidal colonization and candidiasis was studied in a multicenter cohort of 871 human immunodeficiency virus (HIV)-seropositive and 439 demographically and behaviorally similar HIV-seronegative women. Cross-sectional analyses at baseline revealed that oropharyngeal colonization with Candida species was more prevalent among seropositive women and among women reporting recent cigarette smoking and injection drug use. Oropharyngeal candidiasis was also more prevalent among seropositive women. Both oropharyngeal colonization and candidiasis were significantly associated with a lower median CD4 lymphocyte count among seropositive women. Vaginal candidal colonization was more prevalent among seropositive women and among those reporting recent injection drug use and current insulin or oral antihyperglycemic therapy. Vaginal candidiasis was equally likely to be diagnosed in seropositive and seronegative women and was not significantly related to recent sexual contact. Neither vaginal colonization nor candidiasis was significantly related to a lower median CD4 lymphocyte count among seropositive women. Baseline evaluation indicated differences in the epidemiology of oropharyngeal and vaginal candidal colonization and candidiasis in HIV-seropositive women and suggested possible variation in pathogenesis of candidal infection at these two mucosal sites.

Detection and Control of Influenza Outbreaks in Well-Vaccinated Nursing Home Populations

BACKGROUNDnInfluenza outbreaks continue to occur in nursing homes despite high vaccination coverage among residents. Recommendations for outbreak control in institutions such as nursing homes advises use of antiviral drugs to reduce influenza transmission.nnnMETHODSnInfluenza surveillance was performed among elderly residents of nursing homes in Michigan during 2 influenza seasons. The antiviral drug oseltamivir was used for outbreak control at the discretion of nursing home staff once influenza transmission was confirmed by virus isolation or rapid antigen detection.nnnRESULTSnDuring 2000-2001, influenza was not confirmed in any of the 28 participating homes, despite transmission of types A (H1N1) and B in the community. During 2001-2002, influenza type A (H3N2) transmission was confirmed in 8 (26%) of 31 participating homes; influenza vaccine coverage among residents was 57%- 98% in outbreak-associated homes. Oseltamivir was used in all homes with influenza transmission; outbreak control varied according to the rapidity of outbreak recognition and the extent of antiviral use. Reported adverse events were primarily gastrointestinal reactions and rashes. Analysis of the usefulness of rapid antigen detection tests for outbreak recognition indicated a sensitivity of only 77% (specificity, 92%).nnnCONCLUSIONSnOseltamivir was reasonably well tolerated, and its use, along with continued promotion of vaccination coverage among nursing home residents and staff, should be a valuable addition to institutional outbreak-control strategies.

Effectiveness of non-adjuvanted pandemic influenza A vaccines for preventing pandemic influenza acute respiratory illness visits in 4 U.S. communities.

We estimated the effectiveness of four monovalent pandemic influenza A (H1N1) vaccines (three unadjuvanted inactivated, one live attenuated) available in the U.S. during the pandemic. Patients with acute respiratory illness presenting to inpatient and outpatient facilities affiliated with four collaborating institutions were prospectively recruited, consented, and tested for influenza. Analyses were restricted to October 2009 through April 2010, when pandemic vaccine was available. Patients testing positive for pandemic influenza by real-time RT-PCR were cases; those testing negative were controls. Vaccine effectiveness was estimated in logistic regression models adjusted for study community, patient age, timing of illness, insurance status, enrollment site, and presence of high-risk medical conditions. Pandemic virus was detected in 1,011 (15%) of 6,757 enrolled patients. Fifteen (1%) of 1,011 influenza positive cases and 1,042 (18%) of 5,746 test-negative controls had record-verified pandemic vaccination >14 days prior to illness onset. Adjusted effectiveness (95% confidence interval) for pandemic vaccines combined was 56% (23%, 75%). Adjusted effectiveness for inactivated vaccines alone (79% of total) was 62% (25%, 81%) overall and 32% (−92%, 76%), 89% (15%, 99%), and −6% (−231%, 66%) in those aged 0.5 to 9, 10 to 49, and 50+ years, respectively. Effectiveness for the live attenuated vaccine in those aged 2 to 49 years was only demonstrated if vaccination >7 rather than >14 days prior to illness onset was considered (61%∶ 12%, 82%). Inactivated non-adjuvanted pandemic vaccines offered significant protection against confirmed pandemic influenza-associated medical care visits in young adults.