Antibody to Influenza Virus Neuraminidase: An Independent Correlate of Protection.

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.

Efficacy studies of influenza vaccines: effect of end points used and characteristics of vaccine failures.

BACKGROUND: End 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. METHODS: We 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. RESULTS: Although 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. CONCLUSIONS: In 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.

Influenza hemagglutination-inhibition antibody titer as a correlate of vaccine-induced protection.

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. Clinical Trials Registration. NCT00538512.

Influenza transmission in a cohort of households with children: 2010-2011.

BACKGROUND: Households play a major role in community spread of influenza and are potential targets for mitigation strategies. METHODS: 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. RESULTS: 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. DISCUSSION: 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.