A prospective, randomized, open-label trial comparing the safety and efficacy of trivalent live attenuated and inactivated influenza vaccines in adults 60 years of age and older

Background

Although influenza is a major public health concern among adults ≥60 years of age, few large, prospective studies of influenza vaccines have been conducted in this population. The goal of the present study was to directly compare the safety and efficacy of LAIV and TIV in adults ≥60 years of age.

Materials and methods

A prospective, randomized, open-label, multicenter trial was conducted in South Africa. In March-April 2002, 3009 community-dwelling ambulatory adults 60-95 years of age were randomized 1:1 to receive a single dose of LAIV or TIV. Surveillance for influenza illness was conducted through November. Serum antibody titers were evaluated in all participants, and interferon-γ enzyme-linked immunosorbent spot assay responses were evaluated in a cohort of subjects. Solicited reactogenicity and adverse events were monitored for days 0-10 postvaccination; serious adverse events were monitored for the entire study.

Results

Influenza illness caused by vaccine-matched strains was detected in 0.8% (12/1494) and 0.5% (8/1488) of LAIV and TIV recipients, respectively; the relative efficacy of LAIV vs TIV was −49% (95% CI: −259, 35). As expected, greater serum antibody responses were seen with TIV, and greater cellular responses were seen with LAIV (although not for influenza B). Among subjects with culture-confirmed influenza illness, post hoc analyses revealed trends toward less feverishness (LAIV, 14%; TIV, 46%; P = 0.05) and less fever (LAIV, 9%; TIV, 31%; P = 0.16) among LAIV recipients. In each treatment group, 38-39% and 24-25% of subjects had baseline hemagglutination inhibition titers of ≤4 for A/H1 and A/H3, but 7 of 8 TIV cases and 7 of 12 LAIV cases of matched-strain influenza occurred among these subjects. Runny nose/nasal congestion (+13%), cough (+5%), sore throat (+5%), lethargy (+3%), and decreased appetite (+2%) were reported by more LAIV vs TIV recipients. Injection site reactions were reported by 27% of TIV recipients. SAEs were reported by a similar proportion of LAIV and TIV recipients (9% vs 8%).

Conclusions

Given the low incidence of influenza in both groups, no conclusions were possible regarding the relative efficacy of LAIV and TIV. There was a trend toward less feverishness/fever among LAIV recipients who developed influenza compared with TIV recipients with influenza, consistent with results from studies comparing the vaccines in children. A disproportionate number of influenza illnesses occurred among baseline seronegative subjects, particularly for those receiving TIV, which suggests that this subgroup has the greatest need for improved influenza vaccination. The safety profiles of LAIV and TIV were consistent with results from previous studies in older adults and no significant safety concerns were identified.clinicaltrials.gov identifier, NCT00192413.     

The efficacy of intranasal live attenuated influenza vaccine in children 2 through 17 years of age: a meta-analysis of 8 randomized controlled studies

Background

Nine randomized controlled clinical trials, including approximately 26,000 children aged 6 months to 17 years, have evaluated the efficacy of live attenuated influenza vaccine (LAIV) against culture-confirmed influenza illness compared with placebo or trivalent inactivated influenza vaccine (TIV). The objective of the current analysis was to integrate available LAIV efficacy data in children aged 2-17 years, the group for whom LAIV is approved for use.

Methods

A meta-analysis was conducted using all available randomized controlled trials and a fixed-effects model. Cases caused by drifted influenza B were analyzed as originally classified and with all antigenic variants classified as dissimilar.

Results

Five placebo-controlled trials (4 were 2-season trials) and 3 single-season TIV-controlled trials were analyzed. Compared with placebo, year 1 efficacy of 2 doses of LAIV was 83% (95% CI: 78, 87) against antigenically similar strains; efficacy was 87% (95% CI: 78, 93), 86% (95% CI: 79, 91), and 76% (95% CI: 63, 84) for A/H1N1, A/H3N2, and B, respectively. Classifying B variants as dissimilar, efficacy against all similar strains was 87% (95% CI: 83, 91) and 93% (95% CI: 83, 97) against similar B strains. Year 2 efficacy was 87% (95% CI: 82, 91) against similar strains. Compared with TIV, LAIV recipients experienced 44% (95% CI: 28, 56) and 48% (95% CI: 38, 57) fewer cases of influenza illness caused by similar strains and all strains, respectively. LAIV efficacy estimates for children from Europe, the United States, and Middle East were robust and were similar to or higher than those for the overall population.

Conclusions

In children aged 2-17 years, LAIV demonstrated high efficacy after 2 doses in year 1 and revaccination in year 2, and greater efficacy compared with TIV. This meta-analysis provides precise estimates of LAIV efficacy among the approved pediatric age group.     

The effectiveness of trivalent inactivated influenza vaccine in children over six consecutive influenza seasons

Objective

To estimate the effectiveness of two doses of trivalent inactivated influenza vaccine (TIV) over six consecutive influenza seasons in a small community in Japan.

Patients and methods

A prospective, non-randomized, observational study of TIV effectiveness was performed involving children aged 6 months to 6 years accessing pediatric services in Soma and Shinchi, Japan. The total number of children under observation was 14,788. Each fall from 2002 to 2007 TIV was offered to all children with an average uptake of 52.9%. Influenza rapid diagnostic tests were performed to all children with respiratory symptoms and a temperature >38 °C during each surveillance period. The efficacy of two doses of TIV was estimated by the relative risk of influenza illness and influenza associated hospitalizations and effectiveness by reduction in all respiratory illness in vaccinated and unvaccinated children.

Results

Influenza A occurred each year resulting in approximately one in five children in the unvaccinated group having an influenza A related clinic visit. For influenza A, two doses of TIV showed yearly efficacies that ranged from 42% to 69% with the highest efficacy during the 2002/2003 influenza season when the vaccine strains were well matched with the circulating viruses. The overall efficacy of two doses of TIV against influenza A and B associated illness was 52% and 59%, respectively. TIV also reduced the rate of the influenza associated hospitalizations attributable to both influenza A and B.

Conclusions

Vaccination with two doses of TIV was consistently effective in preventing influenza-associated clinic visits and hospitalizations.     

A postlicensure evaluation of the safety of Ann Arbor strain live attenuated influenza vaccine in children 24–59 months of age

Background

In the United States, live attenuated influenza vaccine (LAIV) was initially approved for use in individuals aged 5–49 years in 2003, which was extended to individuals aged 2–49 years in 2007. At that time, a postlicensure commitment was made to describe the safety of LAIV within a cohort of eligible children aged 2–5 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 24–59 months receiving LAIV as part of routine care from October 2007 to March 2010 were compared with rates in a within-cohort self-control, as well as matched unvaccinated and matched trivalent inactivated influenza vaccine (TIV)-vaccinated controls. Children with asthma and other high-risk medical conditions before vaccination were excluded. All MAEs and SAEs through 42 days postvaccination and all hospitalizations and deaths through 6 months postvaccination were analyzed. Statistical significance was declared without multiplicity adjustment.

Results

A total of 28,226 unique LAIV recipients were matched with similar numbers of TIV-vaccinated and unvaccinated children. Of 4696 MAE incidence rate comparisons, 83 (1.8%) were statistically significantly higher and 221 (4.7%) 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.

Conclusions

Results of this postlicensure evaluation of LAIV safety in US children 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 aged 24–59 months who received 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.     

Influenza pandemic (H1N1) 2009 activity during summer 2009. Effectiveness of the 2008-9 trivalent vaccine against pandemic influenza in Spain

Introduction

The Spanish influenza surveillance system (SISS) maintained its activity during the summer of 2009 to monitor the influenza pandemic.

Objectives

To describe pandemic influenza activity from May to September 2009 and to estimate the effectiveness of the 2008-9 seasonal influenza vaccine against laboratory-confirmed pandemic (H1N1) 2009 influenza.

Methods

Data from the SISS were used to identify the trend of pandemic (H1N1) 2009 influenza outside the influenza season. For the effectiveness study, we compared the vaccination status of notified cases [influenza-like illnesses (ILI) laboratory confirmed as pandemic influenza] with that of the test-negative controls.

Results

The first laboratory-confirmed case of the pandemic virus was notified in the system in week 20/2009. The ILI rate increased gradually in the study period, exceeding basic activity in week 38. The proportion of pandemic (H1N1) 2009 influenza viruses detected by the system represented 14% in week 20/2009 and rapidly increased to 90% in week 34. The adjusted vaccine effectiveness of the 2008-9 seasonal vaccine against laboratory-confirmed pandemic influenza was 12% (-30; 41).

Conclusions

The SISS became an essential tool for pandemic monitoring in Spain. The improved SISS will provide more accurate information on influenza activity in future seasonal or pandemic waves. Using surveillance data, we could not demonstrate the effectiveness of the seasonal 2008-9 vaccine against laboratory-confirmed pandemic influenza.     

A randomized, double-blind noninferiority study of quadrivalent live attenuated influenza vaccine in adults

Background

Trivalent seasonal influenza vaccines contain 2 A strains and 1 B strain. B strains of 2 antigenically distinct lineages, Yamagata and Victoria, have been co-circulating annually, and the B strain included in vaccines often has not been a lineage match to the major circulating strain. Thus, a vaccine containing B strains from both lineages could broaden protection against influenza. Quadrivalent live attenuated influenza vaccine (Q/LAIV) is an investigational 4-strain formulation of LAIV that contains 2 A strains, A/H1N1 and A/H3N2, and 2 B strains, 1 from each lineage.

Methods

A randomized, double-blind, active-controlled study of Q/LAIV was conducted in 1800 adults aged 18-49 years to compare the immunogenicity and safety of Q/LAIV to trivalent LAIV (T/LAIV). Subjects were randomized 4:1:1 to receive an intranasal dose of Q/LAIV (n = 1200) or 1 of 2 matching T/LAIV vaccines, each containing 1 of the B strains included in Q/LAIV (n = 600 total). The primary endpoint was the comparison of the post-vaccination strain-specific geometric mean titers (GMT) of hemagglutination inhibition antibody in Q/LAIV recipients to those in T/LAIV recipients, with immunologic noninferiority of Q/LAIV to be demonstrated if the upper bound of the 2-sided 95% confidence interval (CI) for the ratio of the GMTs [T/LAIV divided by Q/LAIV] was ≤1.5 for all strains.

Results and Conclusion

Q/LAIV met the criteria for noninferiority: the ratios of the GMTs for the A/H1N1, A/H3N2, B/Yamagata, and B/Victoria strains were 1.09 (95% CI, 1.01-1.18), 1.05 (95% CI, 0.96-1.14), 1.10 (95% CI, 0.97-1.25), and 0.92 (95% CI, 0.82-1.03), respectively. Solicited symptoms and adverse events were similar in the Q/LAIV and T/LAIV arms. Q/LAIV may confer increased protection against influenza by targeting B strains from both lineages.     

Trivalent influenza vaccine and febrile adverse events in Australia, 2010: clinical features and potential mechanisms

Introduction

Increased numbers of children presenting with febrile adverse events following trivalent influenza vaccine (TIV) were noted in Australia in 2010. We describe the epidemiology and clinical features of the adverse events and explore the biological basis for the adverse events using an in vitro model.

Materials and Methods

Children presenting to a tertiary paediatric hospital in 2010 with adverse events within 72 h of TIV were retrospectively reviewed. Demographics, clinical features, physiological variables and outcomes were examined. Plasma cytokine and chemokine levels were examined in a subgroup of children with vaccine-related febrile convulsions. Peripheral blood mononuclear cells of age-matched children were stimulated with different TIV preparations. Inflammatory cytokine and chemokine analysis was performed on cultured supernatants.

Results

Vaccine-related febrile adverse events were identified in 190 children. Most occurred in healthy children (median age: 1.5 years) within 12 h of vaccination. Twenty-eight (14.7%) required hospital admission. High temperature ≥39.0 °C (101/190; 53%), vomiting (120/190; 63%) and convulsions (38/190; 20%) were common. All children presenting had received Fluvax^® or Fluvax Junior^®.In the in vitro model, IFN-α, IL-1β, IL-6, IL-10, IP-10 and MIP-1α levels were significantly higher when measured at 6 and 24 h in cultures stimulated with Fluvax^® compared with alternative 2010 TIV preparations.

Conclusions

Numerous febrile adverse events (including febrile seizures) were observed following Fluvax^® or Fluvax Junior^® in 2010. Clear differences in cytokine production were observed when peripheral blood mononuclear cells were stimulated with Fluvax^® compared with alternate TIV preparations. Increased awareness of these potential adverse events is required to ensure earlier detection and prevention in the future.     

Inflammatory responses to trivalent influenza virus vaccine among pregnant women

Objective

In the U.S., seasonal trivalent influenza virus vaccine (TIV) is currently universally recommended for all pregnant women. However, data on the maternal inflammatory response to vaccination is lacking and would better delineate the safety and clinical utility of immunization. In addition, for research purposes, vaccination has been used as a mild immune trigger to examine in vivo inflammatory responses in nonpregnant adults. The utility of such a model in pregnancy is unknown. Given the clinical and empirical justifications, the current study examined the magnitude, time course, and variance in inflammatory responses following seasonal influenza virus vaccination among pregnant women.

Methods

Women were assessed prior to and at one day (n = 15), two days (n = 10), or approximately one week (n = 21) following TIV. Serum interleukin (IL)-6, tumor necrosis factor (TNF)-α, C-reactive protein (CRP), and macrophage migration inhibitory factor (MIF) were determined by high sensitivity immunoassay.

Results

Significant increases in CRP were seen at one and two days post-vaccination (ps < 05). A similar effect was seen for TNF-α, for which an increase at two days post-vaccination approached statistical significance (p = .06). There was considerable variability in magnitude of response; coefficients of variation for change at two days post-vaccination ranged from 122% to 728%, with the greatest variability in IL-6 responses at this timepoint.

Conclusions

Trivalent influenza virus vaccination elicits a measurable inflammatory response among pregnant women. There is sufficient variability in response for testing associations with clinical outcomes. As adverse perinatal health outcomes including preeclampsia and preterm birth have an inflammatory component, a tendency toward greater inflammatory responding to immune triggers may predict risk of adverse outcomes, providing insight into biological mechanisms underlying risk. The inflammatory response elicited by vaccination is substantially milder and more transient than seen in infectious illness, arguing for the clinical value of vaccination. However, further research is needed to confirm that the mild inflammatory response elicited by vaccination is benign in pregnancy.     

Influenza vaccination in HIV-infected individuals: Systematic review and assessment of quality of evidence related to vaccine efficacy,effectiveness and safety

Background

Influenza infection in HIV-infected individuals is associated with increased severity of illness. We performed a systematic review of the available evidence on efficacy, effectiveness and safety of seasonal influenza vaccination in HIV-infected individuals.

Design

Systematic review, meta-analysis and assessment of evidence quality.

Methods

Using a previous systematic review as starting point, we searched MEDLINE, EMBASE and Cochrane data base for studies on efficacy, effectiveness or safety of trivalent inactivated influenza vaccines (TIV) in HIV-infected individuals. Evidence quality was assessed for each outcome using the GRADE methodology.

Results

Three randomized-controlled trials and three cohort studies were identified, including a total of 1562 HIV-infected individuals. In adults, TIV prevented laboratory-confirmed influenza with a pooled efficacy of 85% (95% CI, 22–97%) (evidence quality: moderate), but no significant effects on other clinical outcomes were observed (evidence quality: moderate to low). One cohort study showed an effectiveness of 71% (95% CI, 44–85%) for prevention of laboratory-confirmed influenza, whereas no effect on influenza-like illness was found. However, risk of bias was high in all observational studies. In children aged 6–59 months, efficacy of TIV in preventing laboratory-confirmed influenza was 11% (95% CI, −30 to 54%) (evidence quality: moderate). Regarding other endpoints, no statistically significant effects were reported (evidence quality: moderate to low). No severe adverse events following influenza vaccination were observed in these studies.

Conclusion

This systematic review indicates that TIV is effective in preventing influenza infection in HIV-infected adults but not in young children. For both age-groups, only limited evidence exists for other outcomes, indicating a need for further studies.     

Safety, tolerability, and immunogenicity of inactivated trivalent seasonal influenza vaccine administered with a needle-free disposable-syringe jet injector

Background

Jet injectors (JIs) avoid safety drawbacks of needle-syringe (N-S) while generating similar immune responses. A new generation of disposable-syringe jet injectors (DSJIs) overcomes the cross-contamination risk of multi-use-nozzle devices used in 20th-century campaigns. In the first study in humans, the newly-US-licensed LectraJet^® model M3 RA DSJI was compared to N-S.

Methods

Sixty healthy adults received one 0.5 mL intramuscular dose of the 2009-2010 seasonal, trivalent, inactivated influenza vaccine (TIV) in randomized, double-masked fashion by either DSJI (n = 30) or N-S (n = 30). Adverse reactions were monitored for 90 days after injection, and serologic responses assayed by hemagglutination inhibition (HI) at days 28 and 90.

Results

There were no related serious adverse events (SAEs), nor differing rates of unsolicited AEs between DSJI and N-S. Solicited erythema and induration occurred more often after DSJI, but were transient and well-tolerated; a trend was noted for fewer systemic reactions by DSJI. Pre-vaccination HI geometric mean titers (GMT) increased by 28 days for H1N1, H3N2, and B antigens by 13-, 14-, and 8-fold via DSJI, and by 7-, 10-, and 7-fold for N-S, respectively. No trending differences in GMT, seroconversion, or seroprotection were noted; sample sizes precluded non-inferiority assessment.

Conclusions

DSJI delivery of TIV is well-tolerated and immunogenic.     

A postmarketing evaluation of the frequency of use and safety of live attenuated influenza vaccine use in nonrecommended children younger than 5 years

The 2007 US approval for use of live attenuated influenza vaccine (LAIV) in children aged 24-59 months included precautions against use in (1) children <24 months and children aged 24-59 months with (2) asthma, (3) recurrent wheezing, and (4) altered immunocompetence. A postmarketing commitment was initiated to monitor LAIV use and the frequency of select safety outcomes in these cohorts. Vaccination rates and the frequency of hospitalizations or emergency department visits within 42 days after LAIV and trivalent inactivated influenza vaccine (TIV) administration were estimated from 2007 to 2009 claims data from a health insurance database. Rates of LAIV use per 10,000 child-days among cohorts 1, 2, and 4 were low relative to rates among the LAIV-recommended population (2007-2008; 0.03-0.78 vs. 1.32, 2008-2009; 0.08-3.26 vs. 5.94). However, rates of LAIV use per 10,000 child-days in cohort 3 were similar to rates among the LAIV-recommended population (2007-2008; 1.55 vs. 1.32, 2008-2009; 5.01 vs. 5.94). The rate of emergency department visits/hospitalizations within 42 days of vaccination with LAIV was the same as or less than the rate within 42 days of vaccination with TIV. Less restricted LAIV use in children with past wheezing may be related to the broad definition of recurrent wheezing used in national guidelines and the current study. In the small number of nonrecommended children receiving LAIV, no safety signals were identified.     

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.     

Shedding of Ann Arbor strain live attenuated influenza vaccine virus in children 6-59 months of age

Background

A trivalent, Ann Arbor strain, live attenuated influenza vaccine (LAIV) is approved for use in children 24 months of age and older in a number of countries. The incidence, duration, and other parameters of viral shedding after vaccination with LAIV have not been fully described in children ≤5 years of age.

Methods

An open-label, single-arm, multicenter, phase 2 study assessed viral shedding and safety in 200 children 6-59 months of age after a single, intranasal dose of LAIV in 2006. Participants were enrolled into 2 age groups: 6-23 months (n = 100) and 24-59 months (n = 100) of age. Viral shedding, reactogenicity, and adverse events were assessed for 28 days postvaccination. Serious adverse events and significant new medical conditions were monitored for 180 days postvaccination.

Results

Viral shedding was detected by culture in 79% (95% CI, 73-84) of vaccine recipients and occurred more frequently in children 6-23 months of age (89%) compared with children 24-59 months of age (69%). In total, 157 subjects shed vaccine, which was confirmed by RT-PCR as A/H1N1 for 128 subjects, A/H3N2 for 72 subjects, and B for 74 subjects. The incidence of shedding was highest on day 2 (59% in the 6-23 month age group; 41% in the 24-59 month age group) and most shedding occurred 1-11 days postvaccination; shedding after 11 days was infrequent and occurred almost exclusively in children 6-23 months of age. Mean titers of shed vaccine virus peaked on day 2 and were generally <10^3.0 median tissue culture infective dose/mL for both groups. Reactogenicity events peaked on day 2; runny/stuffy nose was reported most frequently (63% of all subjects).

Conclusion

Most children 6-59 months of age vaccinated with Ann Arbor strain LAIV shed ≥1 vaccine virus within 11 days of vaccination. Shedding was less common in children 24-59 months of age, a population for whom LAIV is approved for use. Titers of shed vaccine were low, which may explain why secondary transmission of LAIV was observed very infrequently in a previous controlled study conducted with young children in a daycare setting.     

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).     

Evaluation of the safety, reactogenicity and immunogenicity of FluBlok® trivalent recombinant baculovirus-expressed hemagglutinin influenza vaccine administered intramuscularly to healthy adults 50-64 years of age

Background

Alternative methods for influenza vaccine production are needed to ensure adequate supplies.

Methods

Healthy adults 50-64 years were assigned randomly to receive one intramuscular injection of trivalent recombinant hemagglutinin (rHA) or U.S. licensed trivalent inactivated vaccine (TIV) containing H1, H3 and B antigens (Ag) derived from 2007 to 2008 influenza virus strains A/Solomon Islands/03/2006 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004. Each rHA dose contained 45 μg HA/strain of the 2007-2008 FDA-recommended Ag vs. 15 μg/strain for TIV. Antibody (Ab) responses were measured using a hemagglutination-inhibition (HAI) assay at baseline and 28 days post-vaccination. Respiratory samples for viral culture were collected from subjects with influenza-like illness (ILI) during the 2007-2008 season in the U.S.

Results

601 subjects were enrolled. Vaccines were well tolerated. Seroconversion (the percentage of subjects with either (a) a pre-vaccination HAI titer ≤10 and a post-vaccination HAI titer ≥40 or (b) a pre-vaccination titer ≥10 and a minimum four-fold rise in post-vaccination HAI antibody titer) in the TIV and rHA groups, respectively, was obtained in 66% vs. 72% for H1; 44% vs. 61% for H3; and 41% vs. 41% for B. Proportions achieving titers ≥40 were 96% vs. 96% for H1, 75% vs. 85% for H3, and 94% vs. 93% vs. B. Geometric mean titer ratios at day 28 (TIV/rHA) were 0.77 for H1; 0.58 for H3; and 1.05 for B, respectively. ILI frequencies were low and similar in both groups.

Conclusions

Both vaccines were safe and immunogenic. Ab responses vs. H1 and H3 Ags were significantly higher in the rHA group, with similar responses to B. Furthermore, the FluBlok group had a statistically significantly higher seroconversion rate against influenza A/H3N2 compared to the TIV group.     

Comparison of the safety and immunogenicity of an MF59-adjuvanted with a non-adjuvanted seasonal influenza vaccine in elderly subjects

Aim

Adjuvanted influenza vaccines can overcome the poor antibody response of conventional non-adjuvanted vaccines in the elderly. We evaluated the immunogenicity, safety and clinical effectiveness of an MF59^®-adjuvanted trivalent influenza vaccine (aTIV) compared with a non-adjuvanted vaccine (TIV) in subjects ≥65 years old, with or without co-morbidities.

Methods

In 2010–2011, subjects (N = 7082) were randomized to receive one dose of aTIV or TIV. Co-primary objectives were to assess lot-to-lot consistency of aTIV, non-inferiority, superiority and immunogenicity 22 days after vaccination. Clinical effectiveness, reactogenicity and serious adverse events were monitored up to Day 366.

Results

The immunological equivalence of three lots of aTIV was demonstrated. aTIV was not only non-inferior to TIV but also elicited significantly higher antibody responses at Day 22 than TIV against all homologous and heterologous strains, even in subjects with co-morbidities. Superiority was not established. Reactogenicity was higher in the aTIV group, but reactions were mild to moderate and transient.

Conclusions

aTIV elicited a significantly higher antibody response than TIV, especially against A/H3N2 strains, although superiority by pre-defined criteria was not formally met. The study demonstrates potential immunological benefits of MF59-adjuvanted influenza vaccines for the elderly.This trial was registered with www.clinicaltrials.gov (NCT01162122).     

A US postmarketing evaluation of the frequency and safety of live attenuated influenza vaccine use in nonrecommended children younger than 5 years: 2009-2010 season

The 2007 US approval for use of Ann Arbor strain live attenuated influenza vaccine (LAIV) in children aged 24 through 59 months included precautions against use in (1) children <24 months and children aged 24 through 59 months with (2) asthma, (3) recurrent wheezing, and (4) altered immunocompetence. Results from the third season (2009-2010) of a 3-year study postmarketing commitment to monitor LAIV vaccination rates and frequency of hospitalizations or emergency department visits within 42 days after LAIV are reported here. As in the first 2 seasons, LAIV usage in cohorts 1, 2, and 4 were low relative to those in LAIV-recommended populations. The only numerically increased risk observed was for respiratory events in children aged <24 months administered LAIV, compared to those administered trivalent inactivated influenza vaccine (TIV). The number of children vaccinated with LAIV was small and precluded precise quantification of rare event.