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.     

Efficacy of influenza vaccine for young children in Mie Prefecture in the 1999/2000 prevalent season

PURPOSE: The purpose of this survey was to investigate the efficacy and safety of influenza HA vaccine for children between 1 and 6 years of age in Mie Prefecture during the 1999/2000 prevalent season. METHODS: We surveyed clinical data for children aged between 1 to 6 who visited five clinics in Mie Prefecture. Dividing them into vaccinated and non-vaccinated groups, we surveyed their basic properties, disease histories and manifestation of symptoms. The survey was performed with the consent of parents who were informed of the purpose. We also surveyed the adverse effects within 48 hours after vaccination. The serum HI titers of the vaccinated children were sampled three times: before the first vaccination and after the first and second vaccinations. The data were analysed with the chi-squared test and a multiple logistic model. RESULTS: The frequency of febrile episodes above 38 degrees C was significantly lower in the vaccinated than the non-vaccinated group. While the relative risk for the entire survey period was 0.79, it declined to 0.62 during the peak period of the epidemic. Furthermore, the odds ratio was 0.42 by the multiple logistic model. Among the vaccinated group, the pattern in the increase of HI titer after vaccination varied depending on the species of vaccine antigen. In addition, the frequency of febrile episodes above 38 degrees C was significantly lower in the group which had an HI titer to A/Sydney antigen of 1:40 or more than in these with values below 1:40. CONCLUSION: The relative risk of febrile episodes above 38 degrees C during the influenza prevalent season was 0.62 or below, and vaccine efficacy was 38 percent or above. Considering the significant difference in the frequency of febrile episodes between the groups with HI titers above and below 1:40, it is necessary to study strategies for those with a low response.     

Signal identification and evaluation for risk of febrile seizures in children following trivalent inactivated influenza vaccine in the Vaccine Safety Datalink Project, 2010-2011

In fall 2010 in the southern hemisphere, an increased risk of febrile seizures was noted in young children in Australia in the 24 h after receipt of trivalent inactivated influenza vaccine (TIV) manufactured by CSL Biotherapies. Although the CSL TIV vaccine was not recommended for use in young children in the US, during the 2010-2011 influenza season near real-time surveillance was conducted for febrile seizures in the 0-1 days following first dose TIV in a cohort of 206,174 vaccinated children ages 6 through 59 months in the Vaccine Safety Datalink Project. On a weekly basis, surveillance was conducted with the primary approach of a self-controlled risk interval design and the secondary approach of a current vs. historical vaccinee design. Sequential statistical methods were employed to account for repeated analyses of accumulating data. Signals for seizures based on computerized data were identified in mid November 2010 using a current vs. historical design and in late December 2010 using a self-controlled risk interval design. Further signal evaluation was conducted with chart-confirmed febrile seizure cases using only data from the primary approach (i.e. self-controlled risk interval design). The magnitude of the incidence rate ratio and risk difference comparing risk of seizures in the 0-1 days vs. 14-20 days following TIV differed by receipt of concomitant 13-valent pneumococcal conjugate vaccine (PCV13). Among children 6-59 months of age, the incidence rate ratio (IRR) for TIV adjusted for concomitant PCV13 was 2.4 (95% CI 1.2, 4.7) while the IRR for PCV13 adjusted for concomitant TIV was 2.5 (95% CI 1.3, 4.7). The IRR for concomitant TIV and PCV13 was 5.9 (95% CI 3.1, 11.3). Risk difference estimates varied by age due to the varying baseline risk for seizures in young children, with the highest estimates occurring at 16 months (12.5 per 100,000 doses for TIV without concomitant PCV13, 13.7 per 100,000 doses for PCV13 without concomitant TIV, and 44.9 per 100,000 doses for concomitant TIV and PCV13) and the lowest estimates occurring at 59 months (1.1 per 100,000 doses for TIV without concomitant PCV13, 1.2 per 100,000 doses for PCV13 without concomitant TIV, and 4.0 per 100,000 doses for concomitant TIV and PCV13). Incidence rate ratio and risk difference estimates were lower for children receiving TIV without concomitant PCV13 or PCV13 without concomitant TIV. Because of the importance of preventing influenza and pneumococcal infections and associated complications, our findings should be placed in a benefit-risk framework to ensure that population health benefits are maximized.     

2000/01 influenza season and the vaccine composition for the season 2001/'02]

In the 2000/01 season, the size of the influenza epidemic in the Netherlands was exceptionally small. Since the start of the Continuous Morbidity Registration of the Netherlands Institute of Primary Health Care (NIVEL) in 1970, the peak incidence of influenza-like illnesses has never been so low. The aetiology of the epidemic was also unusual. Most remarkable was the relatively extensive circulation of subtype H1N1 and the low activity of subtype H3N2. The epidemic started in week 1 of 2001 and ended in week 8. The antigenic properties of the influenza A (H1N1) viruses closely resembled those of the vaccine strain A/New Caledonia/20/99. This new variant of subtype H1N1 was first isolated in Asia in 1995 and was only (sporadically) detected in the Netherlands in the 1999/2000 season. Phylogenetic analysis showed that these viruses represent a new line of subtype H1N1. Following the influenza-activity caused by H1N1 viruses in the 2000/01 season, a small number of B and H3N2 viruses were also isolated up to week 19. Antigenically, these viruses were identical to those obtained in the previous years. On the basis of the antigenetic analyses presented, it can be concluded that the vaccine provided good protection against the circulating influenza viruses in the 2000/01 season. The World Health Organization recommends that influenza vaccines intended for use in the 2001/02 season of the northern hemisphere should contain the following, or antigenically similar, strains: A/Moscow/10/99 (H3N2), A/New Caledonia/20/99 (H1N1), and B/Sichuan/379/99.     

Immunogenicity,safety and tolerability of inactivated trivalent influenza vaccine in overweight and obese children

Obesity may be a risk factor for increased hospitalization and deaths from infections due to respiratory pathogens. Additionally, obese patients appear to have impaired immunity after some vaccinations. To evaluate the immunogenicity, safety and tolerability of an inactivated trivalent influenza vaccine (TIV) in overweight and obese children, 28 overweight/obese pediatric patients and 23 healthy normal weight controls aged 3–14 years received a dose of TIV. Four weeks after vaccine administration, significantly higher seroprotection rates against the A/H1N1 strain were observed among overweight/obese children compared with normal weight controls (p < 0.05). Four months after vaccination, similar or slightly higher seroconversion and seroprotection rates against the A/H1N1 and A/H3N2 strains were detected in overweight/obese than in normal weight children, whereas significantly higher rates of seroconversion and seroprotection against the B strain were found in overweight/obese patients than in normal weight controls (p < 0.05 for seroconversion and seroprotection). Geometric mean titers (GMTs) and fold increase against B strains were significantly higher in overweight/obese patients than in normal weight controls 4 months after vaccine administration (p < 0.01 for GMT values and p < 0.05 for fold increase). The frequency of local and systemic reactions was similar between the groups, and there were no serious adverse events. The results of this study indicate that in overweight and obese children, antibody response to TIV administration is similar or slightly higher than that evidenced in normal weight subjects of similar age and this situation persists for at least 4 months after vaccine administration in the presence of a favorable safety profile.     

Interim within-season estimate of the effectiveness of trivalent inactivated influenza vaccine--Marshfield, Wisconsin, 2007-08 influenza season

During clinical trials, the efficacy of vaccination with inactivated influenza vaccines for the prevention of serologically confirmed influenza infection has been estimated as high as 70%-90% among healthier adults. However, the effectiveness of annual influenza vaccination typically is lower during those influenza seasons when a suboptimal match between the vaccine strains and circulating influenza strains is observed. For example, in a 4-year randomized study of influenza vaccine among healthy persons aged 1-65 years, the predominant strain was drifted from the vaccine strain in 2 of the 4 years. Inactivated vaccine effectiveness (VE) against culture-confirmed influenza ranged from 71% to 79% when the vaccine and circulating strains were suboptimally matched to 74% to 79% when the matches were well matched. In contrast, a 2-year study of inactivated influenza vaccine among healthy adults aged 18-64 years found no measurable VE during a year when a poorly matched strain circulated, but found VE of 86% against laboratory-confirmed influenza during the following year when the vaccine and circulating strains were well matched. Although laboratory data on the antigenic characteristics of circulating influenza viruses compared with vaccine strains are available during influenza seasons, estimates of VE usually have not been made until months after the conclusion of the season. This report summarizes interim results of a 2008 case-control study to estimate the effectiveness of trivalent inactivated influenza vaccine for prevention of medically attended, laboratory-confirmed influenza during the 2007-08 influenza season, when most circulating influenza A (H3N2) and B viruses were suboptimally matched to the vaccine strains. Despite the suboptimal match between two of three vaccine strains and circulating influenza strains, overall VE in the study population during January 21-February 8, 2008, was 44%. These findings demonstrate that, in any season, assessment of the clinical effectiveness of influenza vaccines cannot be determined solely by laboratory evaluation of the degree of antigenic match between vaccine and circulation strains.     

Reactogenicity of two 2010 trivalent inactivated influenza vaccine formulations in adults

Objective

To assess the reactogenicity of two 2010 trivalent inactivated influenza vaccine (TIV) formulations among adults, including the formulation associated with febrile convulsions among children in Australia.

Design, setting and participants

We retrospectively interviewed persons aged ≥18 years who received TIV between 11 March and 24 April 2010 at a large general practice in Perth. All 160 persons who received Influvac® (Solvay) and a random sample of 190 of 451 persons who received Fluvax® (CSL Biotherapies) were included in the assessment; 127 (79%) recipients of Influvac® and 156 (82%) of the Fluvax® recipients completed the interview.

Main outcome measures

Patient demographics, the presence of underlying medical conditions, prior influenza vaccination history, self-reported onset of local and/or systemic symptoms within 72 h following receipt of 2010 TIV, and use of anti-fever/pain medication following TIV vaccination were examined.

Results

The mean age of the vaccinees was 54 years for both the Fluvax® and Influvac® brand cohorts and there was no significant difference between the cohorts with regard to gender or the presence of underlying medical conditions. In bivariate analyses, reported swelling (18% vs 7%, p = 0.009), muscle pain (12% vs 3%, p = 0.014) and use of anti-fever/pain medication after TIV vaccination (12% vs 2%, p = 0.008) were each significantly more common for patients who received Fluvax® compared to those who received Influvac®. In multivariate analyses simultaneously controlling for age, gender, receipt of seasonal influenza vaccine prior to 2010 and receipt of 2009 H1N1 pandemic vaccine, vaccination with Fluvax® TIV was a significant independent predictor of muscle pain and/or swelling (OR = 3.3, 95% CI 1.5-7.4 p = 0.004). No significant differences in the proportion of patients reporting systemic reactions were observed.

Conclusions

In this setting, 2010 Fluvax® was associated with a greater likelihood of local reactions among adults, compared to 2010 Influvac® TIV.     

Effectiveness of vaccination against influenza in SkodaAuto Company employees during the influenza season 2000-2001

The SkodaAuto management evaluated the effectiveness of vaccination within the course of the influenza season, 2000 - 2001. All 23,782 company employees working in the plants at Mladá Boleslav, Vrchlabí, and Kvasiny were enrolled into the study, of which 5,079 (21.3%) agreed to be vaccinated against influenza in the autumn, 2000. In comparison with the preceding years, two- to three-fold more employees were vaccinated. During the study period (i.e. between the 4th and 13h week of 2001), 67 (1.3%) individuals from the vaccinated group and 1,297 (6.9%) from the non-vaccinated group fell ill due to influenza or an influenza-like disease (i.e. a five-fold difference). The morbidity peak appeared in the 5th and 6th calendar week with the number of sick reaching nearly 300 during the latter. The morbidity from acute respiratory disease (ARD) in the district of Mladá Boleslav in calendar week 6 was 484 per 10,000 inhabitants which was nearly twice that of the national average. Overall, influenza-related morbidity in the SkodaAuto Company was 4 to 7 times lower than ARD in the Mladá Boleslav district; whereas the respective values in the vaccinated group were up to 10-fold lower. The vaccination effectiveness reached 81.2%.     

Efficacy of live attenuated influenza vaccine against influenza illness in children as a function of illness severity

A recent study of inactivated influenza vaccine (IIV) in children aged 3–8 years demonstrated higher efficacy against moderate/severe influenza. A meta-analysis of all previous published randomized clinical trials of live attenuated influenza vaccine (LAIV) that collected information on illness severity in children aged 24–71 months was conducted. Moderate/severe influenza was defined as fever >39 °C, acute otitis media, or lower respiratory tract illness; other cases were classified as milder influenza. LAIV efficacy versus placebo was 95.4% [95% confidence interval: 88.5, 98.1] (year 1) and 88.5% [77.4, 94.9] (year 2) against moderate/severe influenza and 91.4% [77.9, 96.7] (year 1) and 84.2% [56.7, 94.3] (year 2) against milder influenza. The relative efficacy of LAIV versus IIV was 52.2% [31.6, 66.6] for moderate/severe influenza and 45.0% [28.6, 57.5] for milder influenza. Efficacy against all influenza illnesses, regardless of severity, is critical to prevent influenza illness and transmission in the community.     

Reactogenicity of trivalent inactivated influenza vaccine in young children: Pronounced reactions by previous successive vaccinations

In order to assess factors associated with reactogenicity of trivalent inactivated influenza vaccine (IIV3) among young children, data on 1538 vaccinees aged 0–5 years in a previous vaccine effectiveness study were analyzed.The most frequent reaction was redness (19%), followed by induration, swelling, itching, and pain (6–12%); there were no serious adverse events. For some local reactions, multivariate analyses indicated associations of younger age, preschool attendance, presence of siblings, and allergy with lower risk, and use of thinner needles with higher risk. Most notably, administration of one or more IIV3 vaccines during the previous 3 seasons was positively associated with each local reaction (adjusted odds ratios: 3.6–5.4). For subjects aged ≥3 years, prior successive annual vaccinations were associated with substantially increased local reactions, with clear dose-response relationships (P for trend: <0.001 for each); for example, an 9.8-fold greater risk of swelling following three successive annual vaccinations before the study season.     

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.     

Association of HLA class II genes with clinical hyporesponsiveness to trivalent inactivated influenza vaccine in children

Background

The primary prevention measure for influenza infection has been the use of influenza vaccines. However, even when the vaccine and circulating strains are well-matched, some healthy children do not respond to the vaccine, likely due to a genetic basis for immune hyporesponsiveness. The primary objective of this study was to identify HLA class II genes associated with clinical hyporesponsiveness after trivalent inactivated influenza vaccine (TIV) in children.

Methods

We conducted a case–control study nested within a retrospective cohort of children that were screened at birth for HLA-DR,DQ genotypes by the Diabetes Autoimmunity Study in the Young (DAISY) and were subsequently followed for up to 8 years by Kaiser Permanente, Colorado (KPCO). Hyporesponsiveness was clinically defined as the occurrence of influenza or influenza-like illness (ILI) in peak influenza weeks in children fully vaccinated with TIV. Each child with clinical hyporesponse (n = 252) was matched to 4 randomly selected controls (n = 1006) by age and season. Children with clinical hyporesponse to TIV were identified using the Kaiser electronic clinical and immunization databases. Fully vaccinated children within the KPCO-DAISY cohort who did not have a diagnosis of ILI during the entire influenza season were eligible to be controls for that season. Class II HLA-DRB1 and HLA-DQB1 genes were the primary exposure variables. We used conditional logistic regression to calculate the matched odds ratios.

Results

In non-Hispanic white children, HLA-DR7/4,DQB1*0302 genotype was significantly associated (OR = 5.15; 95% CI = 1.94, 13.67; p = 0.001), while in Hispanic children, HLA-DRB1*15 or 16 allele (OR = 0.31; 95% CI = 0.14, 0.69; p = 0.004) and HLA-DR7/Y (DRB1*11, DRB1*13 and DRB1*14) genotype (OR = 5.84; 95% CI = 1.68, 20.28; p = 0.006) were significantly associated with clinical hyporesponsiveness after TIV.

Conclusions

HLA class II genes are associated with clinical hyporesponsiveness to TIV. This finding is important as it may help identify a group of children who are not protected by the commonly used TIV and may require alternative preventive strategies.     

Immunogenicity, safety and consistency of new trivalent inactivated influenza vaccine

To augment the available influenza vaccine supply, a phase III study was conducted to evaluate the immunogenicity, safety, and consistency of a new trivalent inactivated influenza vaccine manufactured by CSL Limited. Healthy adults (ages 18-64) were randomized to receive either a single dose of TIV from multi-dose vials with thimerosal, TIV from pre-filled syringes without thimerosal, or placebo. Of the TIV recipients, 97.8% achieved a post-vaccination titer > or =40 against H1N1, 99.9% against H3N2 component, and 94.2% against influenza B. Few local or systemic adverse events were noted after vaccination with either TIV presentation. TIV was well tolerated and immunogenic.     

Serious adverse events following receipt of trivalent inactivated influenza vaccine in Korea, 2003-2010

Background

Vaccination is very important for the control and prevention of influenza, yet no vaccine is perfectly safe. Little is known, however, about influenza vaccination-associated serious adverse events following immunization (AEFI). This study aimed to identify background information on influenza vaccination-related serious AEFI in Korea.

Methods

Retrospective review of data from Korea National Vaccine Injury Compensation Program from 2003 to 2010.

Results

Distribution of approximately 75 million doses of influenza vaccine by end of 2010 gave rise to 42 potentially serious AEFI. In all, nine Guillain-Barré syndrome, eighteen other neurologic events, eight local events, and seven miscellaneous events were included. 62% of these events were identified to have unlike causal association with the vaccine. The reporting rate of serious AEFI ranged from 0.006 to 0.07 cases per 100,000 distributed doses of the vaccine.

Conclusion

GBS was the most common influenza vaccination-related serious AEFI. Enhancing post-vaccination GBS surveillance may increase public confidence in future routine and pandemic influenza vaccination.     

Efficacy of trivalent inactivated influenza vaccines in the cotton rat Sigmodon hispidus model

Annually adjusted inactivated influenza vaccines can prevent infection and limit the spread of seasonal influenza when vaccine strain closely matches circulating strain. For the years when the match is difficult to achieve, a rapid screening of a larger repertoire of vaccines may be required but is difficult to accomplish due to the lack of a convenient small animal model of seasonal influenza vaccines. The goal of this work was to determine whether the cotton rat Sigmodon hispidus, a small laboratory animal susceptible to infection with unadapted influenza viruses, may become such a model. Cotton rats were immunized with a trivalent inactivated vaccine (TIV) FluLaval (2006/2007) and vaccine immunogenicity and antiviral efficacy was evaluated against the homologous H1N1 and a heterologous H3N2 challenge. FluLaval induced a strong virus-specific IgG and neutralizing antibody response against homologous virus, elicited sterilizing immunity in the lungs and significantly reduced viral replication in the nose of infected animals. FluLaval was efficacious in cotton rats as either a single-time or a double immunization, although higher level of protection of the upper respiratory tract was achieved following two doses of vaccine. Antibodies against a heterologous influenza strain were induced in FluLaval-vaccinated animals, but vaccine lacked antiviral efficacy and did not reduce replication of a heterologous virus. Similarity of these findings to human TIV data suggests that the cotton rat may prove to be a reliable small animal model of human influenza vaccines.     

Immune response to trivalent inactivated influenza vaccine in young and elderly subjects

The antibody response (determined using the single radial haemolysis in gel technique) to inactivated whole-virion trivalent influenza vaccine [A/Leningrad/360/86(H3N2), A/Taiwan/5/87 and B/Ann Arbor/1/86], recommended for the 1987-88 winter season in Italy, in 49 elderly (age greater than or equal to 60 years) subjects was compared with the response in 23 young adult (age less than 60 years) volunteers. The subjects were prevalently healthy and a high percentage of young and old people had been repeatedly immunized against influenza in previous years. No significant differences were detected among age groups; moreover, the immune response measured by seroconversion or by a significant rise in antibody titre was constantly low.     

Update: influenza activity--United States and worldwide, 1999-2000 season, and composition of the 2000-01 influenza vaccine

Influenza A (H3N2) viruses were the predominant viruses isolated in the United States and worldwide during 1999-2000. This was the third consecutive year that influenza A/Sydney/05/97-like (H3N2) viruses were the most prevalent viruses isolated in the United States. Influenza activity in the United States was similar to the previous two seasons, although mortality measurements attributed to pneumonia and influenza (P&I) were unusually high. Overall, the 1999-2000 influenza vaccine was well matched to circulating influenza viruses. The 2000-01 influenza season will be the first for which influenza vaccination is recommended for all persons aged > or =50 years. This report summarizes surveillance for influenza in the United States and worldwide during the 1999-2000 influenza season, describes the composition of the 2000-01 influenza vaccine, and highlights changes in the recommendations for prevention and control of influenza.