Preclinical safety assessment of a combined vaccine against Hepatitis a virus and enterovirus 71.

Since 2007, Hepatitis A (HAV) vaccination has been a part of the National Immunization Program of China. Recognizing enterovirus 71 (EV71) as the most important pathogen in severe hand, foot and mouth disease, an inactivated EV71 vaccine was successfully marketed in 2015. Based on the concept of one vaccine preventing two diseases and owing to similarities in vaccine preparation and the overlap of the eligible population, a combination of the inactivated HAV vaccine and inactivated EV71 vaccine is theoretically feasible and desirable. However, the optimal vaccinationschedule for this combination vaccine has yet to be optimized. Use of this combined vaccine would not only decrease the number of vaccinations, but also lower associated cost. This study aimed to investigate the toxicity and adverse reactions of the combined HAV-EV71 vaccine under Good Laboratory Practice conditions to provide a reference for clinical studies/applications in the future. CD®(Sprague Dawley) IGS rats were employed for single-dose toxicity testing using a high dose, and repeated-dose toxicity testing using high, as well as low doses. Animals that received only a single dose showed no obvious clinical symptoms nor abnormal body weight, and no significant gross pathological change at the experimental endpoint at necropsy. In the rats injected with three doses, phagocytosis of basophilic granules by macrophages was observed in the inguinal, mesenteric, and local lymph nodes, besides irritation at the administration site. At 56 days after the last dose, no significant histopathological change was observed in the lymph nodes, and local irritation gradually faded. Further, systematic allergy testing was performed in guinea pigs. After systemic sensitization and challenge with the HAV-EV71 vaccine, animals showed normal weight gain and no allergic reactions. This study, therefore, confirmed a good safety profile of the inactivated HAV and EV71 combined vaccine.

Association between inactivated influenza vaccine and primary care consultations for autoimmune rheumatic disease flares: a self-controlled case series study using data from the Clinical Practice Research Datalink.

ObjectivesTo examine the association between inactivated influenza vaccine (IIV) administration and primary care consultation for joint pain, rheumatoid arthritis (RA) flare, corticosteroid prescription, vasculitis and unexplained fever in people with autoimmune rheumatic diseases (AIRDs). METHODS: We undertook within-person comparisons using self-controlled case-series methodology. AIRD cases who received the IIV and had an outcome of interest in the same influenza cycle were ascertained in Clinical Practice Research Datalink. The influenza cycle was partitioned into exposure periods (1-14 days prevaccination and 0-14, 15-30, 31-60 and 61-90 days postvaccination), with the remaining time-period classified as non-exposed. Incidence rate ratios (IRR) and 95% CI for different outcomes were calculated. RESULTS: Data for 14 928 AIRD cases (69% women, 80% with RA) were included. There was no evidence for association between vaccination and primary care consultation for RA flare, corticosteroid prescription, fever or vasculitis. On the contrary, vaccination associated with reduced primary care consultation for joint pain in the subsequent 90 days (IRR 0.91 (95% CI 0.87 to 0.94)). CONCLUSION: This study found no evidence for a significant association between vaccination and primary care consultation for most surrogates of increased disease activity or vaccine adverse-effects in people with AIRDs. It adds to the accumulating evidence to support influenza vaccination in AIRDs.

Challenges in conducting a community-based influenza vaccine trial in a rural community in northern India.

Evidence on influenza vaccine effectiveness from low and middle countries (LMICs) is limited due to limited institutional capacities; lack of adequate resources; and lack of interest by ministries of health for influenza vaccine introduction. There are concerns that the highest ethical standards will be compromised during trials in LMICs leading to mistrust of clinical trials. These factors pose regulatory and operational challenges to researchers in these countries. We conducted a community-based vaccine trial to assess the efficacy of live attenuated influenza vaccine and inactivated influenza vaccine in rural north India. Key regulatory challenges included obtaining regulatory approvals, reporting of adverse events, and compensating subjects for trial-related injuries; all of which were required to be completed in a timely fashion. Key operational challenges included obtaining audio-visual consent; maintaining a low attrition rate; and administering vaccines during a narrow time period before the influenza season, and under extreme heat. We overcame these challenges through advanced planning, and sustaining community engagement. We adapted the trial procedures to cope with field conditions by conducting mock vaccine camps; and planned for early morning vaccination to mitigate threats to the cold chain. These lessons may help investigators to confront similar challenges in other LMICs.

Assessment of an optimized manufacturing process for inactivated quadrivalent influenza vaccine: a phase III, randomized, double-blind, safety and immunogenicity study in children and adults.

BACKGROUND: GSK has modified the licensed monovalent bulk manufacturing process for its split-virion inactivated quadrivalent influenza vaccine (IIV4) to harmonize the process among different strains, resulting in an increased number of finished vaccine doses, while compensating for the change from inactivated trivalent influenza vaccine (IIV3) to IIV4. To confirm the manufacturing changes do not alter the profile of the vaccine, a clinical trial was conducted to compare IIV4 made by the currently licensed process with a vaccine made by the new (investigational) process (IIV4-I). The main objectives were to compare the reactogenicity and safety of IIV4-I versus IIV4 in all age groups, and to demonstrate the non-inferiority of the hemagglutination-inhibition (HI) antibody responses based on the geometric mean titer ratio of IIV4-I versus IIV4 in children. METHODS: The Phase III, randomized, double-blind, multinational study included three cohorts: adults (18-49 years; N = 120), children (3-17 years; N = 821), and infants (6-35 months; N = 940). Eligible subjects in each cohort were randomized 1:1 to receive IIV4-I or IIV4. Both vaccines contained 15 µg of hemagglutinin antigen for each of the four seasonal virus strains. Adults and vaccine-primed children received one dose of vaccine, and vaccine-unprimed children received two doses of vaccine 28 days apart. All children aged ≥9 years were considered to be vaccine-primed and received one dose of vaccine. RESULTS: The primary immunogenicity objective of the study was met in demonstrating immunogenic non-inferiority of IIV4-I versus IIV4 in children. The IIV4-I was immunogenic against all four vaccine strains in each age cohort. The reactogenicity and safety profile of IIV4-I was similar to IIV4 in each age cohort, and there was no increase in the relative risk of fever (≥38 °C) with IIV4-I versus IIV4 within the 7-day post-vaccination period in infants (1.06; 95% Confidence Interval: 0.75, 1.50; p = 0.786). CONCLUSIONS: The study demonstrated that in adults, children, and infants, the IIV4-I made using an investigational manufacturing process was immunogenic with a reactogenicity and safety profile that was similar to licensed IIV4. These results support that the investigational process used to manufacture IIV4-I is suitable to replace the current licensed process. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02207413 ; trial registration date: August 4, 2014.

Comprehensive safety assessment of a human inactivated diploid enterovirus 71 vaccine based on a phase III clinical trial.

Human enterovirus 71 (EV71) is a causative agent of hand, foot, and mouth disease (HFMD). In a previous phase III trial in children, a human diploid cell-based inactivated EV71 vaccine elicited EV71 specific immune responses and protection against EV71 associated HFMD. This study aimed to assess the factors influencing the severity of adverse events observed in this previous trial. This was a randomized, double-blinded, placebo-controlled, phase III clinical trial of a human diploid vaccine carried out in 12,000 children in Guangxi Zhuang Autonomous Region, China (ClinicalTrials.gov: NCT01569581). Solicited events were recorded for 7 days and unsolicited events were reported for 28 days after each injection. Age trend analysis of adverse reaction was conducted in each treatment group. Multiple logistic regression models were built to identify factors influencing the severity of adverse reactions. Fewer solicited adverse reactions were observed in older participants within the first 7 days after vaccination (P < 0.0001), except local pain and pruritus. More severe adverse reactions were observed after the initial injection than after the booster injection. Serious cold or respiratory tract infections (RTI) were observed more often in children aged 6-36 months than in older children. Only the severity of local swelling was associated with body mass index. Children with throat discomfort before injection had a higher risk of serious cold or RTI. These results indicated that the human diploid cell-based vaccine achieved a satisfactory safety profile.

Characterization of a novel oil-in-water emulsion adjuvant for swine influenza virus and Mycoplasma hyopneumoniae vaccines.

Vaccines consisting of subunit or inactivated bacteria/virus and potent adjuvants are widely used to control and prevent infectious diseases. Because inactivated and subunit antigens are often less antigenic than live microbes, a growing need exists for the development of new and improved vaccine adjuvants that can elicit rapid and long-lasting immunity. Here we describe the development and characterization of a novel oil-in-water emulsion, OW-14. OW-14 contains low-cost plant-based emulsifiers and was added to antigen at a ratio of 1:3 with simple hand mixing. OW-14 was stable for prolonged periods of time at temperatures ranging from 4 to 40°C and could be sterilized by autoclaving. Our results showed that OW-14 adjuvanted inactivated swine influenza viruses (SIV; H3N2 and H1N1) and Mycoplasma hyopneumoniae (M. hyo) vaccines could be safely administered to piglets in two doses, three weeks apart. Injection sites were monitored and no adverse reactions were observed. Vaccinated pigs developed high and prolonged antibody titers to both SIV and M. hyo. Interestingly, antibody titers were either comparable or greater than those produced by commercially available FluSure (SIV) or RespiSure (M. hyo) vaccines. We also found that OW-14 can induce high antibody responses in pigs that were vaccinated with a decreased antigen dose. This study provides direct evidence that we have developed an easy-to-use and low-cost emulsion that can act as a powerful adjuvant in two common types of swine vaccines.

Immunogenicity and safety assessment of a trivalent, inactivated split influenza vaccine in Korean children: Double-blind, randomized, active-controlled multicenter phase III clinical trial.

A multicenter, double-blind, randomized, active-control phase III clinical trial was performed to assess the immunogenicity and safety of a trivalent, inactivated split influenza vaccine. Korean children between the ages of 6 months and 18 y were enrolled and randomized into a study (study vaccine) or a control vaccine group (commercially available trivalent, inactivated split influenza vaccine) in a 5:1 ratio. Antibody responses were determined using hemagglutination inhibition assay, and post-vaccination immunogenicity was assessed based on seroconversion and seroprotection rates. For safety assessment, solicited local and systemic adverse events up to 28 d after vaccination and unsolicited adverse events up to 6 months after vaccination were evaluated. Immunogenicity was assessed in 337 and 68 children of the study and control groups. In the study vaccine group, seroconversion rates against influenza A/H1N1, A/H3N2, and B strains were 62.0% (95% CI: 56.8-67.2), 53.4% (95% CI: 48.1-58.7), and 54.9% (95% CI: 48.1-60.2), respectively. The corresponding seroprotection rates were 95.0% (95% CI: 92.6-97.3), 93.8% (95% CI: 91.2-96.4), and 95.3% (95% CI: 93.0-97.5). The lower 95% CI limits of the seroconversion and seroprotection rates were over 40% and 70%, respectively, against all strains. Seroconversion and seroprotection rates were not significantly different between the study and control vaccine groups. Furthermore, the frequencies of adverse events were not significantly different between the 2 vaccine groups, and no serious vaccination-related adverse events were noted. In conclusion, the study vaccine exhibited substantial immunogenicity and safety in Korean children and is expected to be clinically effective.

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.

Assessment of an oral Mycobacterium bovis BCG vaccine and an inactivated M. bovis preparation for wild boar in terms of adverse reactions, vaccine strain survival, and uptake by nontarget species.

Wildlife vaccination is increasingly being considered as an option for tuberculosis control. We combined data from laboratory trials and an ongoing field trial to assess the risk of an oral Mycobacterium bovis BCG vaccine and a prototype heat-inactivated Mycobacterium bovis preparation for Eurasian wild boar (Sus scrofa). We studied adverse reactions, BCG survival, BCG excretion, and bait uptake by nontarget species. No adverse reactions were observed after administration of BCG (n = 27) or inactivated M. bovis (n = 21). BCG was not found at necropsy (175 to 300 days postvaccination [n = 27]). No BCG excretion was detected in fecal samples (n = 162) or in urine or nasal, oral, or fecal swab samples at 258 days postvaccination (n = 29). In the field, we found no evidence of loss of BCG viability in baits collected after 36 h (temperature range, 11°C to 41°C). Camera trapping showed that wild boar (39%) and birds (56%) were the most frequent visitors to bait stations (selective feeders). Wild boar activity patterns were nocturnal, while diurnal activities were recorded for all bird species. We found large proportions of chewed capsules (29%) (likely ingestion of the vaccine) and lost baits (39%) (presumably consumed), and the proportion of chewed capsules showed a positive correlation with the presence of wild boar. Both results suggest proper bait consumption (68%). These results indicate that BCG vaccination in wild boar is safe and that, while bait consumption by other species is possible, this can be minimized by using selective cages and strict timing of bait deployment.

Manufacturers' postmarketing safety surveillance of influenza vaccine exposure in pregnancy.

Pregnant women are at increased risk for hospitalization and death with influenza infection. The limited data on safety and effectiveness of influenza immunization in pregnancy emphasizes the importance of developing new and well-designed studies and of enhancing safety surveillance in pregnant women who are vaccinated with licensed influenza vaccines. Pregnancy exposure registries aim to collect and maintain data on the effects of marketed drugs and vaccines, when prescribed in pregnancy or during breastfeeding, on the women themselves and their children. Women who are prescribed a medication or vaccine as part of their routine clinical care can be enrolled directly or through reporting health care providers on a voluntary basis. Such registries generally are established for products that are intended for use by adolescents and adults and are a key component of the safety monitoring of licensed products. This article reviews some of the pregnancy registries that have been established for US-licensed vaccines, which includes influenza vaccines, and other postlicensure safety surveillance efforts for monitoring safety in vaccinated pregnant women.

Phase 2 assessment of the safety and immunogenicity of two inactivated pandemic monovalent H1N1 vaccines in adults as a component of the U.S. pandemic preparedness plan in 2009.

BACKGROUND: The influenza A/H1N1 pandemic in 2009 created an urgent need to develop vaccines for mass immunization. To guide decisions regarding the optimal immunization dosage and schedule for adults, we evaluated two monovalent, inactivated, unadjuvanted H1N1 influenza vaccines in independent, but simultaneously conducted, multi-center Phase 2 trials of identical design. METHODS: Healthy adults, stratified by age (18-64 years and ≥65 years), were randomized (1:1 allocation), in a double-blind, parallel-group design, to receive two intramuscular doses (21 days apart) of vaccine containing approximately 15 µg or 30 µg of hemagglutinin (HA). Primary endpoints were safety (reactogenicity for 8 days after each vaccination and vaccine-associated serious adverse events during the 7 month study) and immunogenicity (proportion of subjects, stratified by age, achieving a serum hemagglutination inhibition [HI] antibody titer ≥1:40 or a ≥4-fold rise in titer after a single injection of either dosage). RESULTS: Both vaccines were well-tolerated. A single 15 µg dose induced HI titers ≥1:40 in 90% of younger adults (95% confidence interval [CI] 82-95%) and 81% of elderly (95% CI 71-88%) who received Sanofi-Pasteur vaccine (subsequently found to contain 24 µg HA in the standard potency assay), and in 80% of younger adults (95% CI 71-88%) and 60% of elderly (95% CI 50-70%) who received CSL vaccine. Both vaccines were significantly more immunogenic in younger compared with elderly adults by at least one endpoint measure. Increasing the dose to 30 µg raised the frequency of HI titers ≥1:40 in the elderly by approximately 10%. Higher dosage did not significantly enhance immunogenicity in younger adults and a second dose provided little additional benefit to either age group. CONCLUSION: These trials provided evidence for policymakers that a single 15 µg dose of 2009 A/H1N1 vaccine would likely protect most U.S. adults and suggest a potential benefit of a 30 µg dose for the elderly.

Safety of trivalent inactivated influenza vaccine in children aged 24 to 59 months in the vaccine safety datalink.

OBJECTIVES: To evaluate the safety of trivalent inactivated influenza vaccine (TIV) in children aged 24 to 59 months and to evaluate the risk of medically attended events (MAEs) in a subcohort of children who had multiple annual doses of TIV over their lifetimes. DESIGN: Self-controlled screening study. SETTING: Seven US managed care organizations from October 1, 2002, to March 31, 2006. PARTICIPANTS: Children aged 24 to 59 months who received at least 1 TIV dose (66 283 children and 91 692 TIV doses). EXPOSURE: Vaccination with TIV. MAIN OUTCOME MEASURES: Medically attended events in inpatient and emergency department settings in one of the following risk windows: 0 to 2, 1 to 14, or 1 to 42 days after vaccination. All MAEs that met the screening criteria of incidence rate ratios (IRRs) exceeding 1.0 and P ≤ .05 or IRRs exceeding 2.0 and P < .20 underwent medical record review. A secondary analysis examined the risk of MAEs in children who had multiple annual lifetime TIV doses. RESULTS: Nine diagnoses met the screening criteria. After medical record review, gastrointestinal tract symptoms (IRR, 1.18; 95% confidence interval [CI], 1.10-1.25), gastrointestinal tract disorders (7.70; 1.11-53.52), and fever (1.71; 1.64-1.80) remained significantly associated with vaccination. None of the events seemed to be serious, and none had complications. In the secondary analysis, there was an apparent dose response for vaccine and allergic reactions in the 1- to 3-day risk window. CONCLUSIONS: There was no evidence of serious MAEs following vaccination with TIV among children aged 24 to 59 months. Further studies are warranted to evaluate the risk of MAEs in children with multiple lifetime TIV doses.

Is it time for a new yellow fever vaccine?

An inexpensive live attenuated vaccine (the 17D vaccine) against yellow fever has been effectively used to prevent yellow fever for more than 70 years. Interest in developing new inactivated vaccines has been spurred by recognition of rare but serious, sometimes fatal adverse events following live virus vaccination. A safer inactivated yellow fever vaccine could be useful for vaccinating people at higher risk of adverse events from the live vaccine, but could also have broader global health utility by lowering the risk-benefit threshold for assuring high levels of yellow fever vaccine coverage. If ongoing trials demonstrate favorable immunogenicity and safety compared to the current vaccine, the practical global health utility of an inactivated vaccine is likely to be determined mostly by cost.

Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010.

This report updates the 2009 recommendations by CDC's Advisory Committee on Immunization Practices (ACIP) regarding the use of influenza vaccine for the prevention and control of influenza (CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2009;58[No. RR-8] and CDC. Use of influenza A (H1N1) 2009 monovalent vaccine---recommendations of the Advisory Committee on Immunization Practices [ACIP], 2009. MMWR 2009;58:[No. RR-10]). The 2010 influenza recommendations include new and updated information. Highlights of the 2010 recommendations include 1) a recommendation that annual vaccination be administered to all persons aged >or=6 months for the 2010-11 influenza season; 2) a recommendation that children aged 6 months--8 years whose vaccination status is unknown or who have never received seasonal influenza vaccine before (or who received seasonal vaccine for the first time in 2009-10 but received only 1 dose in their first year of vaccination) as well as children who did not receive at least 1 dose of an influenza A (H1N1) 2009 monovalent vaccine regardless of previous influenza vaccine history should receive 2 doses of a 2010-11 seasonal influenza vaccine (minimum interval: 4 weeks) during the 2010--11 season; 3) a recommendation that vaccines containing the 2010-11 trivalent vaccine virus strains A/California/7/2009 (H1N1)-like (the same strain as was used for 2009 H1N1 monovalent vaccines), A/Perth/16/2009 (H3N2)-like, and B/Brisbane/60/2008-like antigens be used; 4) information about Fluzone High-Dose, a newly approved vaccine for persons aged >or=65 years; and 5) information about other standard-dose newly approved influenza vaccines and previously approved vaccines with expanded age indications. Vaccination efforts should begin as soon as the 2010-11 seasonal influenza vaccine is available and continue through the influenza season. These recommendations also include a summary of safety data for U.S.-licensed influenza vaccines. These recommendations and other information are available at CDC's influenza website (http://www.cdc.gov/flu); any updates or supplements that might be required during the 2010-11 influenza season also will be available at this website. Recommendations for influenza diagnosis and antiviral use will be published before the start of the 2010-11 influenza season. Vaccination and health-care providers should be alert to announcements of recommendation updates and should check the CDC influenza website periodically for additional information.

In vitro assessment of the allergenicity of a novel influenza vaccine produced in dog kidney cells in individuals with dog allergy.

BACKGROUND: An inactivated influenza vaccine produced in canine kidney cells (MDCK 33016-PF) contains no egg proteins and may be used to immunize egg-allergic patients. Although no major dog allergens were identified in MDCK 33016-PF cells, minor dog allergens might be present and cause reactions in dog-allergic individuals. OBJECTIVE: To evaluate the allergenicity of the inactivated influenza vaccine produced in cell culture in a mediator release assay. METHODS: Rat basophil leukemia (RBL) cells transfected with human IgE receptor-1 were sensitized with sera from dog-allergic adults with positive skin prick test reactions to dog extract and detectable dog dander IgE and were stimulated with serial dilutions of vaccine and dog dander extract. N-hexosaminidase release (NHR) was used as a marker of RBL cell degranulation. Western blots were performed, and UniCAP was used to measure dog-specific IgE antibody levels. RESULTS: The median (interquartile range) level of dog dander IgE was 8.31 kU(A)/L (1.895-14.5 kU(A)/L) and of dog epithelium IgE was 3.19 kU(A)/L (0.835-6.27 kU(A)L). Median (range) maximum NHR (at the first 10-fold dilution) was 0% (0%-1.4%) to vaccine and 10.2% (0%-35.9%) to dog dander (P < .001). In an egg-allergic control subject, the maximum NHR to a vaccine cultured in chick embryo and containing egg protein was 10.2%. IgE antibodies in pooled sera did not bind to vaccine on immunoblots but produced strong binding to dog dander and epithelium extracts. Serum from an egg-allergic control subject strongly bound embryonated egg-derived vaccine. CONCLUSION: An influenza vaccine produced in continuous canine kidney cells did not trigger degranulation in RBL cells passively sensitized with human anti-dog IgE.

Vaccines against pandemic influenza: what can be done before the next pandemic?

We currently do not know which specific influenza subtype or isolate will cause the next influenza pandemic. However, 4 influenza virus hemagglutinin subtypes (H2, H5, H7, and H9) are considered the most likely candidates. Avian influenza viruses of the H5N1 subtype have received the most attention to this point, as their ability to spread within the human population remains the only barrier to emergence of a pandemic strain. Several vaccines have been tested against these potential pandemic viruses using standard methods for developing inactivated vaccines. In general, these vaccines have been poorly immunogenic, requiring high doses and multiple exposures to generate even modest antibody titers. The use of adjuvants to improve presentation of antigen and stimulate the immune system offers promise for enhanced immunity. Currently approved adjuvants, MF59 and Alum, can be readily incorporated into pandemic vaccines, while novel adjuvants are moving toward approval, but may still be years away from routine use. Thus, a prepandemic vaccine strategy that involves the stockpiling of both potential antigens and proven adjuvants may represent the best approach to deal with this looming threat.

Cost-effectiveness of live attenuated influenza vaccine versus inactivated influenza vaccine among children aged 24-59 months in the United States.

BACKGROUND: The US Advisory Committee on Immunization Practices (ACIP) recently expanded the influenza vaccine recommendation to include children 24-59 months of age. In a large head-to-head randomized controlled trial, live attenuated influenza vaccine, trivalent (LAIV) demonstrated a 54% relative reduction in culture-confirmed influenza illness compared with trivalent inactivated influenza vaccine (TIV) among children aged 24-59 months. OBJECTIVE: To evaluate the relative cost and benefit between two influenza vaccines (LAIV and TIV) for healthy children 24-59 months of age. METHODS: Using patient-level data from the clinical trial supplemented with cost data from published literature, we modeled the cost-effectiveness of these two vaccines. Effectiveness was measured in quality-adjusted life years (QALY) and cases of influenza avoided. The analysis used the societal perspective. RESULTS: Due to its higher acquisition cost, LAIV increased vaccination costs by USD7.72 per child compared with TIV. However, compared with TIV, LAIV reduced the number of influenza illness cases and lowered the subsequent healthcare use of children and productivity losses of parents. The estimated offsets in direct and indirect costs saved USD15.80 and USD37.72 per vaccinated child, respectively. LAIV had a net total cost savings of USD45.80 per child relative to TIV. One-way and probabilistic sensitivity analyses indicated that the model was robust across a wide range of relative vaccine efficacy and cost estimates. CONCLUSIONS: Due to its increased relative vaccine efficacy over TIV, LAIV reduced the burden of influenza and lowered both direct health care and societal costs among children 24-59 months of age.

Health benefits, risks, and cost-effectiveness of influenza vaccination of children.

We estimated cost-effectiveness of annually vaccinating children not at high risk with inactivated influenza vaccine (IIV) to range from US $12,000 per quality-adjusted life year (QALY) saved for children ages 6-23 months to $119,000 per QALY saved for children ages 12-17 years. For children at high risk (preexisting medical conditions) ages 6-35 months, vaccination with IIV was cost saving. For children at high risk ages 3-17 years, vaccination cost $1,000-$10,000 per QALY. Among children notat high risk ages 5-17 years, live, attenuated influenza vaccine had a similar cost-effectiveness as IIV. Risk status was more important than age in determining the economic effects of annual vaccination, and vaccination was less cost-effective as the child's age increased. Thus, routine vaccination of all children is likely less cost-effective than vaccination of all children ages 6-23 months plus all other children at high risk.