A study to evaluate the immunogenicity and shedding of live attenuated influenza vaccine strains in children 24–<48 months of age

BackgroundQuadrivalent live attenuated influenza vaccine (LAIV4) showed reduced effectiveness against the A/H1N1 component in the 2013–2014 and 2015–2016 influenza seasons. The most likely cause of reduced LAIV effectiveness against A(H1N1)pdm09 strains was poor intranasal replication.ObjectivesTo compare the immunogenicity and shedding of a new A/H1N1 strain (A/Slovenia), to a A/H1N1 strain known to have reduced effectiveness (A/Bolivia).Patients/methodsThis was a randomized, double-blind, multicenter study. Children aged 24–<48 months of age were randomized 1:1:1 to receive two doses of LAIV4 2017–2018 (LAIV4_A/Slovenia), or LAIV4 2015–2016 or trivalent LAIV (LAIV3) 2015–2016 formulations (LAIV4_A/Bolivia or LAIV3_A/Bolivia, respectively) on days 1 and 28. The primary endpoint was strain-specific hemagglutination inhibition (HAI) antibody seroresponse at 28 days post each dose, and secondary endpoints included immunogenicity, shedding, and safety. Solicited symptoms, adverse events (AEs), and serious AEs (SAEs) were recorded. Pre-specified statistical testing was limited to the primary endpoint of HAI antibody responses.ResultsA total of 200 children were randomized (median age 35.3 months; 53% male; 57% had previously received influenza vaccine). Significantly higher HAI antibody responses for the A/Slovenia strain were observed after Dose 1 and Dose 2. Neutralizing antibodies and nasal immunoglobulin A antibody responses were higher for A/Slovenia versus A/Bolivia. More children shed the A/Slovenia vaccine strain than the A/Bolivia strain on Days 4–7 after Dose 1. No deaths, SAEs, or discontinuations from vaccine occurred.ConclusionsThe new A(H1N1)pdm09 A/Slovenia LAIV strain demonstrated improved immunogenicity compared with a previous strain with reduced effectiveness and induced immune responses comparable to a highly efficacious pre-pandemic H1N1 LAIV strain. These results support the use of LAIV4 containing A/Slovenia as a vaccine option in clinical practice.     

Shedding of live vaccine virus, comparative safety, and influenza-specific antibody responses after administration of live attenuated and inactivated trivalent influenza vaccines to HIV-infected children

HIV-infected children (N=243), >or=5 to <18 years old, receiving stable antiretroviral therapy, were stratified by immunologic status and randomly assigned to receive intranasal live attenuated influenza vaccine (LAIV) or intramuscular trivalent inactivated influenza vaccine (TIV). The safety profile after LAIV or TIV closely resembled the previously reported tolerability to these vaccines in children without HIV infection. Post-vaccination hemagglutination inhibition (HAI) antibody responses and shedding of LAIV virus were also similar, regardless of immunological stratum, to antibody responses and shedding previously reported for children without HIV infection. LAIV should be further evaluated for a role in immunizing HIV-infected children.     

Comparative analysis of influenza A(H3N2) virus hemagglutinin specific IgG subclass and IgA responses in children and adults after influenza vaccination

Two different influenza vaccines are generally used in many countries; trivalent live attenuated influenza vaccine (LAIV3) and trivalent inactivated influenza vaccine (IIV3). Studies comparing the antibody response to IIV3 and LAIV3 commonly investigate the seroprotective response by hemagglutination-inhibition (HI) assay. However, there is limited data regarding comparative analysis of IgG subclass and IgA responses induced by LAIV3 and IIV3.Fifteen children <5 years received 2 doses of LAIV3 while 14 children aged 10–17 years received one dose. In addition, 15 adults were vaccinated with either intranasal LAIV3 or intramuscular IIV3. We analyzed the H3N2 humoral responses by HI assay and the hemagglutinin (HA) specific IgG1, IgG2, IgG3, IgG4 and IgA1 responses by ELISA. Furthermore, we investigated the avidity of induced IgG antibodies.Pre-existing seroprotective HI antibodies were present in adults (73%) previously vaccinated with IIV3. Vaccination resulted in a significant increase in HI titers in all groups, except LAIV3 vaccinated adults. Furthermore, a negative correlation between age and HI titers in LAIV3 vaccinated subjects was observed post-vaccination. LAIV3 in children and IIV3 in adults induced HA-specific IgG1, low IgG3 but no IgG2 or IgG4. Moreover, significant IgA1 responses were only induced in children. Interestingly, IIV3 and LAIV3 induced IgG antibodies with comparable and significantly augmented avidity post-vaccination in children and adults.Our results suggest that age and/or exposure history play a significant role in determining the antibody response.Clinical trial registry: ClinicalTrials.gov NCT01003288 and NCT01866540     

Responses to live attenuated influenza vaccine in children vaccinated previously with Pandemrix (ASO3B adjuvanted pandemic A/H1N1pdm09)

BackgroundWe report a phase III/IV open-label study on the immunogenicity of a single dose of a Live Attenuated Influenza Vaccine (LAIV) (Fluenz™) in children naïve to, or in previous receipt of, AS03_B adjuvanted A/H1N1pdm09 influenza vaccine (Pandemrix™), to investigate whether early exposure to an adjuvanted subunit influenza vaccine impacts on subsequent response to quadrivalent LAIV (qLAIV).Method and findingsEligible children were enrolled to receive qLAIV and stratified according to previous Pandemrix™ vaccination. Functional antibody for the vaccine strains were analysed using Haemagglutination Inhibition (HAI); in addition antibodies to the A/H1N1pdm09 strain were measured by Neuraminidase Antibody Inhibition (NAI) and neutralisation assays. Fourfold titre increases by HAI were observed for 39% (95% confidence interval 33–46%) and 43% (37–51%) of subjects for the two influenza B vaccine strains and 8% (5–13%) for the A/H3N2 strain with no significant differences between the Pandemrix™ naïve or previously vaccinated groups in antibody tites pre- or post-vaccination or seroconversion rates. In both groups, the response to the qLAIV A/H1N1pdm09 component was barely detectable, overall HAI seroconversion rate 1.8% (0.5–4.7%). Previous receipt of Pandemrix™ was associated with significantly higher levels of A/H1N1pdm09 neutralising antibody, but decreased NAI titres pre-vaccination, with the differences maintained post-vaccination.ConclusionPrevious receipt of Pandemrix™ has had a significant impact on the influenza immune status of children several years later. Higher levels of neutralising antibody to A/H1N1pdm09 pre- and post-vaccination, but significantly lower levels of antibody to NA, were observed compared with Pandemrix™-naïve children, while responses to influenza B and A/H3N2 and antibody levels prior to vaccination were similar in both groups. This suggests that early vaccination with a powerful adjuvant maintains functional immunity for several years, which prevents natural infection. Alternatively, the AS03_B adjuvant may have re-directed the immune response, with focus towards viral HA and away from viral NA.     

The role of nasal IgA in children vaccinated with live attenuated influenza vaccine

Background

Immunoglobulin A (IgA) is the predominant antibody produced in response to mucosal infections. The role of IgA in providing protection against influenza in children vaccinated with live attenuated influenza vaccine (LAIV) has not been well described.

Methods

Nasal IgA responses were assessed using data from 3 prospective, 2-year, randomized studies comparing LAIV with placebo in children 6–36 months of age. In each study, samples were collected in a subset of patients; a new cohort was enrolled each year. Ratios of strain-specific nasal IgA to total nasal IgA were calculated and prevaccination to postvaccination geometric mean fold-rises (GMFRs) were evaluated. Mean postvaccination IgA ratios were compared for subjects with and without confirmed influenza illness by study and in pooled analyses.

Results

Across studies, a higher percentage of children receiving LAIV had a ≥2-fold increase in strain-specific IgA ratio compared with placebo recipients. GMFRs after LAIV in years 1 and 2 ranged from 1.2 to 6.2, compared with 0.5–2.2 among placebo recipients. Similar responses were observed in subjects who were baseline seronegative and seropositive based on serum hemagglutination inhibition antibody titers. In years 1 and 2, the mean postvaccination strain-specific to total IgA ratio was 3.1-fold (P < 0.01) and 2.0-fold (P < 0.03) higher among LAIV recipients with no evidence of culture-confirmed influenza illness compared with LAIV recipients who developed culture-confirmed influenza illness; a similar and consistent trend was observed for each individual study and type/subtype.

Conclusions

The current analysis demonstrates that nasal IgA contributes to the efficacy of LAIV and can provide evidence of vaccine-induced immunity. However, the inherent heterogeneity in nasal antibody levels and variability in nasal specimen collection hinders the precise evaluation of mucosal antibody responses. Other studies have demonstrated that LAIV-induced immunity is also partially explained by T-cell immunity, serum antibody responses, and innate immunity, consistent with the multi-faceted nature of immunity induced by wild-type influenza infection and other live virus vaccines.     

Safety of Russian-backbone seasonal trivalent,live-attenuated influenza vaccine in a phase II randomized placebo-controlled clinical trial among children in urban Bangladesh

IntroductionLive-attenuated influenza vaccines (LAIVs) have the potential to be affordable, effective, and logistically feasible for immunization of children in low-resource settings.Material and methodsWe conducted a phase II, randomized, double-blind, parallel group, placebo-controlled trial on the safety of the Russian-backbone, seasonal trivalent LAIV among children aged 24 through 59 months in Dhaka, Bangladesh in 2012. After vaccination, we monitored participants for six months with weekly home visits and study clinic surveillance for solicited and unsolicited adverse events, protocol-defined wheezing illness (PDWI), and serious adverse events (SAEs), including all cause hospitalizations.ResultsThree hundred children were randomized and administered LAIV (n = 150) or placebo (n = 150). No immediate post-vaccination reactions occurred in either group. Solicited reactions were similar between vaccine and placebo groups during the first 7 days post-vaccination and throughout the entire trial. There were no statistically significant differences in participants experiencing PDWI between LAIV and placebo groups throughout the trial (n = 13 vs. n = 16, p = 0.697). Of 131 children with a history of medical treatment or hospitalization for asthma or wheezing at study entry, 65 received LAIV and 66 received placebo. Among this subset, there was no statistical difference in PDWI occurring throughout the trial between the LAIV or placebo groups (7.7% vs. 19.7%, p = 0.074). While there were no related SAEs, LAIV recipients had six unrelated SAEs and placebo recipients had none. These SAEs included three due to traumatic injury and bone fracture, and one each due to accidental overdose of paracetamol, abdominal pain, and acute gastroenteritis. None of the participants with SAEs had laboratory-confirmed influenza, wheezing illness, or other signs of acute respiratory illness at the time of their events.ConclusionsIn this randomized, controlled trial among 300 children aged 24 through 59 months in urban Bangladesh, Russian-backbone LAIV was safe and well tolerated. Further evaluation of LAIV safety and efficacy in a larger cohort is warranted.     

Safety and immunogenicity of a quadrivalent inactivated influenza vaccine compared to licensed trivalent inactivated influenza vaccines in adults

Purpose

To evaluate the safety and immunogenicity of a prototype quadrivalent inactivated influenza vaccine (QIV) containing two influenza B strains, one of each lineage, compared with licensed trivalent inactivated influenza vaccines (TIVs) containing either a Victoria B-lineage strain (2009–2010 TIV) or a Yamagata B-lineage strain (2008–2009 TIV).

Methods

Healthy adults ≥18 years of age were eligible to participate in this phase II, open-label, randomized, controlled, multicenter study conducted in the US. Participants received a single dose of 2009–2010 TIV, 2008–2009 TIV, or QIV. Sera were collected before and 21 days after vaccine administration to test for hemagglutination inhibition (HAI) antibodies to each of the four influenza strains. Immunogenicity endpoints included geometric mean HAI antibody titers (GMTs) and rates of seroprotection (titer ≥1:40) and seroconversion (4-fold rise pre- to post-vaccination). Safety endpoints included frequency of solicited injection-site and systemic reactions occurring within 3 days of vaccination, and unsolicited non-serious adverse events (AEs) and serious AEs (SAEs) within 21 days of vaccination.

Results

One hundred and ninety participants were enrolled to each vaccine group. QIV induced GMTs to each A and B strain that were noninferior to those induced by the 2009–2010 and 2008–2009 TIVs (i.e., lower limit of the two-sided 95% confidence interval of the ratio of GMT_QIV/GMT_TIV > 0.66 for each strain). Rates of seroprotection and seroconversion were similar in all groups. Incidence and severity of solicited injection-site and systemic reactions, AEs, and SAEs were similar among groups.

Conclusion

QIV, containing two B strains (one from each B lineage), was as safe and immunogenic as licensed TIV. QIV has the potential to be a useful alternative to TIV and offer protection against both B lineages.     

Antibody-dependent cell-mediated cytotoxicity antibody responses to inactivated and live-attenuated influenza vaccination in children during 2014–15

BackgroundSeasonal influenza vaccines aim to induce strain-specific neutralizing antibodies. Non-neutralizing antibodies may be more broadly cross-reactive and still protect through mechanisms including antibody-dependent cell-mediated cytotoxicity (ADCC). Influenza vaccines may stimulate ADCC antibodies in adults, but whether they do so in children is unknown. Here we examined how vaccination affects cross-reactive ADCC antibody responses in children after receipt of inactivated trivalent vaccine (IIV3) or quadrivalent live-attenuated vaccine (LAIV4).MethodsChildren aged 5–17 were recruited in fall 2014 to provide pre- and post-vaccination serum samples. Children aged 5–9 received LAIV4 based on then-current recommendation, and older children were randomly assigned to IIV3 or LAIV4. We used microtiter-plate-based flow cytometry with an NK cell line to examine ADCC antibody responses to the 2014–15 H3N2 vaccine component (A/Texas/50/2012 [TX12]) and a drifted strain, A/Switzerland/9715293/2013 (SW13). Responses were stratified by two-season (2013–14 and 2014–15) vaccine sequence.ResultsEighty-five children received LAIV4 and 45 received IIV3. Prevaccination ADCC activity was highest in children who had received any vaccine in the prior season. Increase in ADCC antibody responses against the vaccine strain TX12 following vaccination was greatest for participants who received IIV3 in 2014–15 and LAIV4 in the prior season (geometric mean fold rise [MFR] = 1.6, 95% CI.1.23–2.11). This group also had a detectable ADCC response to the drifted SW13 strain. There was a modest ADCC response against SW13 in LAIV4 recipients who were unvaccinated in the previous season (MFR = 1.18, 95% CI 1.10–1.25). There were no significant changes in 2014–15 ADCC response to vaccination among children who had received IIV3 in 2013–14.ConclusionsVaccinating children with IIV3 after prior receipt of LAIV4 generated a modest increase in ADCC antibodies, including some cross-reactivity with an emerging drift variant. Other vaccine-induced ADCC responses were minimal and not affected by vaccine type or sequence.     

A randomized controlled trial of antibody response to 2019–20 cell-based inactivated and egg-based live attenuated influenza vaccines in children and young adults

BackgroundHemagglutination inhibition (HAI) titers to the live-attenuated influenza vaccine (LAIV4) are typically lower than its counterpart egg-based inactivated influenza vaccines (IIV). Similar comparisons have not been made between LAIV4 and the 4-strain, cell-culture inactivated influenza vaccine (ccIIV4). We compared healthy children’s and young adults’ HAI titers against the 2019–2020 LAIV4 and ccIIV4.MethodsParticipants aged 4–21 years were randomized 1:1 to receive ccIIV4 (n = 100) or LAIV4 (n = 98). Blood was drawn prevaccination and on day 28 (21–35) post vaccination. HAI assays against egg-grown A/H1N1, A/H3N2, both vaccine B strains and cell-grown A/H3N2 antigens were conducted. Primary outcomes were geometric mean titers (GMT) and geometric mean fold rise (GMFR) in titers.ResultsGMTs to A/H1N1, A/H3N2 and B/Victoria increased following both ccIIV and LAIV and to B/Yamagata following ccIIV (p < 0.05). The GMFR range was 2.4–3.0 times higher for ccIIV4 than for LAIV4 (p < 0.001). Within vaccine types, egg-grown A/H3N2 GMTs were higher (p < 0.05) than cell-grown GMTs [ccIIV4 day 28: egg = 205 (95% CI: 178–237); cell = 136 (95% CI:113–165); LAIV4 day 28: egg = 96 (95% CI: 83–112); cell = 63 (95% CI: 58–74)]. The GMFR to A/H3N2 cell-grown and egg-grown antigens were similar. Pre-vaccination titers inversely predicted GMFR.ConclusionThe HAI response to ccIIV4 was greater than LAIV4 in this study of mostly older children, and day 0 HAI titers inversely predicted GMFR for both vaccines. Lower prevaccination titers were associated with greater GMFR in both vaccine groups.     

Safety and immunogenicity of seasonal trivalent inactivated influenza vaccines in pregnant women

BackgroundIn the United States, seasonal inactivated influenza vaccine (IIV) is recommended for pregnant women; however, in early 2009, immunization rates were low, partly due to limited prospective data and concerns about vaccine safety.ObjectiveWe conducted a randomized study of two licensed seasonal trivalent IIVs (IIV3) to assess their safety and immunogenicity in pregnant women.Study DesignIn this prospective, randomized clinical study, 100 pregnant women, 18–39 years of age and ≥14 weeks gestation received a single intramuscular dose of 2008–2009 Fluzone® or Fluarix®. Injection site and systemic reactions were recorded for 7 days after vaccination and serious adverse events (SAEs) and pregnancy outcomes were documented. Serum samples collected before and 28 days after vaccination were tested for hemagglutination inhibition (HAI) antibody levels.ResultsThe majority of the injection site and systemic reactions were mild and self-limited after both vaccines. No fever ≥100 °F was reported. There were no vaccine-associated SAEs. Immune responses to influenza vaccine antigens were similar for the two study vaccines, with robust HAI responses against influenza A strains, and relatively lower responses for influenza B strains.ConclusionSeasonal inactivated influenza vaccines were well tolerated and immunogenic in pregnant women.

• ClinicalTrials.gov identifier NCT00905125.

Synopsis: In this prospective clinical trial, we demonstrated that immunization with seasonal trivalent, inactivated influenza vaccine in the second and third trimester of pregnancy is immunogenic and safe.     

Safety of quadrivalent live attenuated influenza vaccine in subjects aged 2–49 years

BackgroundQuadrivalent live attenuated influenza vaccine (Q/LAIV) was licensed in 2012 and replaced trivalent live attenuated influenza vaccine in the United States during the 2013–2014 influenza season. This study assessed the safety of Q/LAIV in children and adults aged 2–49 years.MethodsThis was a prospective observational cohort study using data collected from Kaiser Permanente Northern California. Post-vaccination events of interest were any hospitalization, hospitalization for lower respiratory tract infection, and the following medically attended events: hypersensitivity, seizures/convulsions, lower respiratory tract infection, wheezing, Guillain-Barré syndrome, Bell’s palsy, encephalitis, neuritis, vasculitis, and narcolepsy/cataplexy. The rates of these events during the risk interval post-vaccination were compared with rates observed during reference periods later in the follow-up (within-cohort analysis) and with rates observed in frequency-matched unvaccinated controls and inactivated influenza vaccine (IIV) recipients.ResultsA total of 62,040 eligible Q/LAIV recipients were identified during the 2013–2014 influenza season. Within-cohort comparisons of all Q/LAIV recipients as well as comparisons between Q/LAIV recipients and unvaccinated controls or IIV recipients did not show any significantly higher risk of hospitalizations or medically attended events following administration of Q/LAIV. Additional analyses by setting (clinic visits, emergency department visits, and hospital admissions) and age group (2–4, 5–8, 9–17, and 18–49 years) also did not reveal clinically consistent findings that suggested any increased risk after administration of Q/LAIV.ConclusionIn this large population study of individuals aged 2–49 years, no safety signals associated with the administration of Q/LAIV were observed. A much larger study population would be needed to confidently reject any association between Q/LAIV and very rare events, specifically those with an incidence of <1 event/10,000 person-years.Trial registration: ClinicalTrials.gov NCT01985997     

Priming with MF59 adjuvanted versus nonadjuvanted seasonal influenza vaccines in children – A systematic review and a meta-analysis

BackgroundIdentifying optimal priming strategies for children <2 years could substantially improve the public health benefits of influenza vaccines. Adjuvanted seasonal influenza vaccines were designed to promote a better immune response among young vaccine-naïve children.MethodsWe systematically reviewed randomized trials to assess hemagglutination inhibition (HAI) antibody response to MF59-adjuvanted inactivated influenza vaccine (aIIV) versus nonadjuvanted IIV among children. We estimated pooled ratios of post-vaccination HAI geometric mean titer (GMT) for aIIV versus IIV and confidence intervals (CIs) using the pooled variances derived from reported CIs.ResultsMean age was 28 months (range, 6–72 months). Children received vaccines with either 7.5 μg (6–35 months) or 15 μg (≥36 months) hemagglutinin of each strain depending on age. Seven of eight trials administered trivalent vaccines and one used quadrivalent vaccine. Pooled post-vaccination GMT ratios against the three influenza vaccine strains were 2.5–3.5 fold higher after 2-dose-aIIV versus 2-dose-IIV among children 6–72 months, and point estimates were higher among children 6–35 months compared with older children. When comparing 1-dose-aIIV to 2-dose-IIV doses, pooled GMT ratios were not significantly different against A/H1N1 (1.0; 95% CI: 0.5–1.8; p = 0.90) and A/H3N2 viruses (1.0; 95% CI: 0.7–1.5; p = 0.81) and were significantly lower against B viruses (0.6; 95% CI: 0.4–0.8; p < 0.001) for both age groups. Notably, GMT ratios for vaccine-mismatched heterologous viruses after 2-dose-aIIV compared with 2-dose-IIV were higher against A/H1N1 (2.0; 95% CI: 1.1–3.4), A/H3N2 (2.9; 95% CI: 1.9–4.2), and B-lineage viruses (2.1; 95% CI: 1.8–2.6).ConclusionsTwo doses of adjuvanted IIV consistently induced better humoral immune responses against Type A and B influenza viruses compared with nonadjuvanted IIVs in young children, particularly among those 6–35 months. One adjuvanted IIV dose had a similar response to two nonadjuvanted IIV doses against Type A influenza viruses. Longer-term benefits from imprinting and cell-mediated immunity, including trials of clinical efficacy, are gaps that warrant investigation.     

Nanoemulsion W805EC improves immune responses upon intranasal delivery of an inactivated pandemic H1N1 influenza vaccine

Currently available influenza vaccines provide suboptimal protection. In order to improve the quality of protective immune responses elicited following vaccination, we developed an oil-in-water nanoemulsion (NE)-based adjuvant for an intranasally-delivered inactivated influenza vaccine. Using a prime-boost vaccination regimen, we show that intranasal vaccines containing the W₈₀5EC NE elicited higher titers of serum hemagglutination inhibiting (HAI) antibody and influenza-specific IgG and IgA titers compared to vaccines that did not contain the NE. Similarly, vaccines containing the W₈₀5EC NE resulted in higher influenza-specific IgA levels in the bronchoalveolar lavage (BAL) fluid and nasal wash when compared to vaccines formulated without NE. The higher antibody titers in mice immunized with the NE-containing vaccines correlated with reduced viral loads in the lungs and nasal turbinates following a high dose viral challenge. Mice immunized with vaccines containing the W₈₀5EC NE also showed a reduction in body weight loss following challenge compared to mice immunized with equivalent vaccines produced without NE. Taken together, our results show that the W₈₀5EC NE substantially improves the magnitude of protective influenza-specific antibody responses and is a promising mucosal adjuvant for influenza vaccines and vaccines against other mucosal pathogens.     

Safety of live attenuated influenza vaccine in mild to moderately immunocompromised children with cancer

Background

The safety of intranasal live-attenuated influenza vaccine (LAIV) in immunocompromised children with cancer is unknown. The objective of this study was to describe the safety and immunogenicity of LAIV in mild to moderately immunocompromised children with cancer.

Methods

We conducted a multicenter, randomized, double-blind study of LAIV versus placebo in children aged 5-17 years with cancer. LAIV (frozen formulation) or allantoic fluid/buffer was administered intranasally. Reactogenicity, adverse events, blood for immune assays, and nasal swabs for viral shedding were obtained during 5 visits over the first 42 days postvaccination; information concerning serious adverse events (SAEs) was collected for 180 days.

Results

20 subjects were enrolled (LAIV, n = 10; placebo, n = 10) with a mean age of 12.2 years. Ten subjects had hematologic malignancy (LAIV, n = 4; placebo, n = 6); 10 subjects had solid tumors (LAIV, n = 6; placebo, n = 4). One subject was excluded from immunogenicity analysis for not receiving a full dose of LAIV. LAIV resulted in an increased incidence of runny nose/nasal congestion occurring in all LAIV recipients; no related SAEs were observed. Four of 10 LAIV recipients shed vaccine virus, with none exceeding 7-10 days duration. LAIV demonstrated modest immunogenicity by hemagglutination inhibition (≥4 fold rise for any strain, 33%) and microneutralization assays (≥4 fold rise for any strain, 44%).

Conclusion

In this small pilot study conducted in mild to moderately immunocompromised children with cancer, runny nose/nasal congestion was increased in LAIV recipients, no related SAEs occurred, and prolonged viral shedding was not detected. Moderate immunogenicity was demonstrated in this small group of individuals. (ClinTrials.gov: NCT00112112).     

A postmarketing evaluation of the safety of Ann Arbor strain live attenuated influenza vaccine in adults 18-49 years of age

Background

The Ann Arbor strain-live attenuated influenza vaccine (LAIV) was licensed in 2003 for use in the United States for individuals aged 5–49 years of age. As part of a postmarketing commitment to safety, LAIV was studied in adults 18–49 years participating in the Kaiser Permanente Health Plan over 5 influenza seasons.

Methods

Individuals received LAIV as part of routine care from October 2003 through March 2008. Using Kaiser Permanente databases, rates of medically attended events (MAEs) and serious adverse events (SAEs) in LAIV recipients were compared with rates in multiple non-randomized control groups which included a self-control group, matched unvaccinated controls, and matched controls vaccinated with inactivated influenza vaccine (TIV).

Results

A total of 21,340, 18,316, and 21,340 subjects received LAIV, TIV and no vaccine, respectively. More than 5500 MAE incidence rate comparisons were performed, and of these, 257 (5%) yielded statistically significant differences with 72 and 185 occurring at a higher and lower rate after LAIV compared with control groups, respectively. The pattern of MAE rate differences did not suggest any safety signal associated with LAIV. There were 47 SAEs noted, and no individual SAE occurred at a significantly higher or lower rate in LAIV recipients relative to control groups in any comparison. Only 2 SAEs (migraine/sinusitis and Bell's palsy) were considered possibly or probably related to LAIV.

Conclusion

The results of this post-licensure evaluation of LAIV safety in individuals 18–49 years of age are consistent with pre- and post-approval clinical studies as well as reports to the U.S. Vaccine Adverse Events Reporting System, all of which demonstrated no significant adverse outcomes among eligible individuals following receipt of LAIV.     

A postmarketing evaluation of the safety of Ann Arbor strain live attenuated influenza vaccine in children 5 through 17 years of age

Background

Live attenuated influenza vaccine (LAIV) was licensed in 2003 in the United States for use in individuals aged 5–49 years.

Methods

A prospective observational postmarketing study was conducted to evaluate the safety of LAIV. Rates of medically attended events (MAEs) and serious adverse events (SAEs) in eligible children aged 5–17 years receiving LAIV as part of routine care from October 2003 to March 2008 were compared with rates in nonrandomized self, matched unvaccinated, and matched trivalent inactivated influenza vaccine (TIV)-vaccinated controls. All MAEs and SAEs through 42 days postvaccination and all hospitalizations and deaths through 6 months postvaccination were analyzed. Statistical significance was assigned without multiplicity adjustment.

Results

43,702 LAIV recipients were matched with similar numbers of TIV-vaccinated and unvaccinated children. Of approximately 9500 MAE incidence rate comparisons, 204 were statistically significantly higher and 168 were statistically significantly lower in LAIV recipients versus controls. No pattern of MAE rate differences suggested a safety signal with LAIV. Asthma/wheezing MAEs were not statistically increased in LAIV recipients. No anaphylaxis events occurred within 3 days postvaccination. Rates of SAEs were similar between LAIV and control groups. Two SAEs were considered possibly related to LAIV: Bell's palsy and nonspecific paroxysmal spell.

Conclusions

Results of this postlicensure evaluation of LAIV safety in US children aged 5–17 years are consistent with preapproval clinical studies and Vaccine Adverse Event Reporting System reports, both of which demonstrated no significant increase in asthma/wheezing events or other adverse outcomes among eligible children who received LAIV.     

Randomized evaluation of live attenuated vs. inactivated influenza vaccines in schools (RELATIVES) pilot study: A cluster randomized trial

BackgroundSchool-based influenza immunization can effectively address accessibility barriers, but injected inactivated influenza vaccines (IIV) may not be acceptable to some children and parents in school settings.ObjectivesTo better understand the feasibility of offering intranasal live attenuated influenza vaccines (LAIV) through schools, we assessed uptake, stakeholder acceptability, and cost of school-based delivery of LAIV compared to IIV.MethodsWe piloted an open-label cluster randomized trial involving 10 elementary schools in Peterborough, Ontario during the 2013–2014 influenza vaccination campaign. Schools were randomized to having students receive IIV or LAIV at publicly-funded school-based clinics organized by the local public health department. We measured the percentage of students vaccinated with at least one dose of influenza vaccine at school. Stakeholder acceptability was evaluated through a questionnaire of parents and interviews of public health department personnel and school principals. We compared the costs per dose of vaccine administered, including staff time and costs of vaccines and supplies.ResultsSingle-dose influenza vaccine uptake was higher for the five schools offering LAIV than for the five offering IIV (19.3% vs. 12.2%, p = 0.02). Interviews with nine school principals and five public health department personnel suggested that the clinics ran smoothly with little disruption to school routines, and that LAIV was associated with increased efficiency and calmer children. All interviewees cited unfamiliarity with LAIV and the study recruitment package length as potential reasons for low uptake. The cost per vaccine dose administered was $38.67 for IIV and $43.50 for LAIV.ConclusionsUse of LAIV in school-based clinics was associated with increased vaccine uptake and the perception among immunizing staff of reduced child anxiety, but also slightly higher vaccine administration costs, compared to IIV. However, uptake was low for both groups. More effective strategies to promote influenza vaccines and to obtain parent consent may improve vaccine uptake.Trial registrationClinicalTrials.gov NCT01995851.FundingPublic Health Agency of Canada/Canadian Institutes of Health Research Influenza Research Network.     

Influenza vaccines effectiveness 2013–14 through 2015–16, a test-negative study in children

BackgroundTrivalent inactivated and live attenuated influenza vaccines (IIV3 and LAIV3) have been reformulated with an extra B strain (IIV4 and LAIV4). They were licensed based on immunogenicity and their effectiveness (VE) still must be empirically tested.MethodsChildren 1–17 years tested for influenza during 2013–16 were included and their immunization status verified. They were considered vaccinated if received ≥1 dose of an influenza vaccine ≥10 days before evaluated for a respiratory episode. Age-groups were classified as 1–4 years or 5–17 years. VE was estimated by comparing vaccination status of influenza-positive versus influenza-negative cases.Results6779 children were enrolled in the three seasons. Overall, 27.2% received an influenza vaccine (87.1% IIV3 or IIV4 and 12.9% LAIV4), and 15.6% tested positive for influenza (77.9% A). IIV3 was predominantly used in 2013–14 and IIV4 in 2014–15 and 2015–16. IIV3 and IIV4 had comparable VE over the three seasons (60%, 57% and 53%) and performed similarly against influenza A and B and both age-groups. LAIV4 performed poorly for influenza A (15%, 37% and 48%) but better for influenza B (100%, 56% and 100%), especially among children 5–17 years of age with VE = 100% (95%CI: 55, 100).ConclusionsInfluenza vaccination showed modest but consistent effectiveness over the years. The switch from IIV3 to IIV4 did not affect VE. LAIV4 did not perform as well as IIVs, yet it improved over the years and was particularly good protecting older children against influenza B. These results emphasize the regional nature of influenza and the need for local surveillance.     

The induction of CD80 and apoptosis on B cells and CD40L in CD4+ T cells in response to seasonal influenza vaccination distinguishes responders versus non-responders in healthy controls and aviremic ART-treated HIV-infected individuals

BackgroundStudies have shown that HIV infection is associated with an impaired influenza vaccine response. We examined the role of cellular phenotypes and function in influenza vaccine responsiveness in healthy controls and aviremic HIV-infected subjects on antiretroviral treatment (ART).Methods16 healthy controls and 26 ART+ aviremic HIV+ subjects were enrolled in the current study. Blood was collected at pre-vaccination (D0), and on days 7–10 (D7) and 14–21 (D14) following the 2013–2014 seasonal influenza vaccine administrations. Subjects were classified as responders if neutralizing titers against H1N1 virus increased ⩾4-fold at D14 compared to D0. A serial analysis of B and CD4+ T cell frequencies and activation was performed on D0 and D7 by flow cytometry.Results9 of 26 (34.6%) HIV-infected individuals and 7 of 16 (43.8%) healthy controls were classified as responders to influenza vaccines. Total B cell apoptosis (annexin V) was increased on D7 post-vaccination in non-responders but not in responders among both controls and HIV+ subjects. Surface CD80 expression on memory B cells and intracellular CD40L expression on memory CD4+ T cells were induced on D7 in responders of controls but not in non-responders. The CD80 and CD40L induction was not demonstrable in HIV-infected subjects regardless of responders and non-responders. Memory CD4+ T cell cycling tended to increase on D7 in the four study groups but did not achieve significance. All the other parameters were indistinguishable between responders and non-responders, regardless of HIV-infection status.ConclusionThe perturbation of activation and apoptotic induction on B cells or CD4+ T cells after seasonal influenza vaccination in non-responders and HIV-infected subjects may help understand the mechanism of impaired vaccine responsiveness.