Immunogenicity,reactogenicity, and safety of inactivated quadrivalent influenza vaccine candidate versus inactivated trivalent influenza vaccine in healthy adults aged ≥18 years: A phase III,randomized trial

Background

Two influenza B lineages have been co-circulating since the 1980s, and because inactivated trivalent influenza vaccine (TIV) contains only one B strain, it provides little/no protection against the alternate B-lineage. We assessed a candidate inactivated quadrivalent influenza vaccine (QIV) containing both B lineages versus TIV in healthy adults.

Methods

Subjects received one dose of QIV (lot 1, 2, or 3) or one of two TIVs (B strain from Victoria or Yamagata lineage); randomization was 2:2:2:1:1. Hemagglutination-inhibition assays were performed 21-days post-vaccination; superiority of QIV versus TIV for the alternate B-lineage was demonstrated if the 95% confidence interval (CI) lower limit for the GMT ratio was ≥1.5, and non-inferiority against the shared strains was demonstrated if the 95% CI upper limit for the GMT ratio was ≤1.5. Reactogenicity and safety were assessed during the post-vaccination period. NCT01196975.

Results

Immunogenicity of QIV lots was consistent, QIV was superior to TIV for the alternate B-lineage strain, and QIV was non-inferior versus TIVs for shared strains (A/H1N1, A/H3N2, B-strain). Reactogenicity and safety profile of the QIV was consistent with seasonal influenza vaccines.

Conclusion

QIV provided superior immunogenicity for the added B strain without affecting the antibody response to the TIV strains, and without compromising safety.     

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.     

A Phase III randomised trial of the immunogenicity and safety of quadrivalent versus trivalent inactivated subunit influenza vaccine in adult and elderly subjects,assessing both anti-haemagglutinin and virus neutralisation antibody responses

BackgroundTrivalent influenza vaccines (TIVs) offer substantial protection against matching B-strains, however, protection against alternate-lineage B-strains may be enhanced by adding a second B-strain in quadrivalent influenza vaccines (QIVs). In this Phase III, double-blind, multicentre, randomised study, the immunogenicity and safety of subunit inactivated QIV versus TIV was assessed in adult (aged ≥18 to ≤60 years) and elderly (aged ≥61 years) subjects by analysing a combination of haemagglutinin inhibition (HI) and virus neutralisation (VN).MethodsSubjects (n = 1980) were recruited off season (2015/2016) from 20 centres in five European countries and randomised to receive either QIV (n = 1538), TIV with B-strain of the Victoria lineage (n = 221) or TIV with B-strain of the Yamagata lineage (n = 221). The primary aim was to demonstrate non-inferiority of QIV to TIV for immunogenicity against matched influenza strains based on post-vaccination HI titres. Secondary aims were to show superiority of QIV to TIV for immunogenicity against alternate-lineage B-strains and to characterise the immune response by reverse cumulative distribution (RCD) curves of antibody titres and derived serological parameters for HI and VN. Reactogenicity and occurrence of adverse events were assessed post-vaccination.ResultsQIV elicited a non-inferior immune response for matched strains (upper limit of 95% CI for HI geometric mean ratios [GMRs] <1.5) and a superior response for alternate-lineage B-strains (HI GMRs < 1; p < 0.0001) versus TIV. RCD curves demonstrated that post-vaccination HI and VN titres were higher for QIV versus TIV for both alternate-lineage B-strains. Seroconversion rates and geometric mean fold increases of the VN assay were consistent with the HI assay for all strains in QIV. Reporting rates of local and systemic reactions were similar in both vaccine groups.ConclusionsQIV was non-inferior in immunogenicity to TIV for matched strains and superior to the alternate-lineage B-strains in TIV. Safety and tolerability profiles of QIV and TIV were comparable.     

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).     

Priming by a novel universal influenza vaccine (Multimeric-001)—A gateway for improving immune response in the elderly population

Background

A new vaccine, “Multimeric-001” (M-001) has been recently developed, containing conserved, common linear influenza epitopes that activate both cellular and humoral arms of the immune system against a wide variety of influenza A and B strains. Apart from its direct action, M-001 is an attractive candidate for priming immune responses to seasonal influenza vaccine for the elderly population. The current clinical study was designed to assess M-001's standalone and priming action in participants over 65 years old. Evaluation of standalone action is based on induction of cell mediated immunity (CMI), since M-001 alone does not induce hemagglutinin inhibition (HAI) antibodies.

Methods

This was a two-center, randomized, placebo-controlled study. 120 participants were randomized 1:1:1:1 into four groups to receive either two sequential non-adjuvanted or a single non-adjuvanted or a single adjuvanted intramuscular injection of 500 mcg M-001 (treatment), or one placebo (saline) injection, before receiving the trivalent inactivated influenza vaccine (TIV). Due to visual differences between placebo and treatment the study was partially blinded. HAI was evaluated at baseline and 3 weeks after standard TIV vaccination as a measure of M-001's efficacy. CMI responses were evaluated in a subset (10/group) of the participants. Participants were monitored for safety throughout the study.

Results

Overall the treatment was well-tolerated and safe, though sample sizes allowed only limited statistical analysis. M-001 priming resulted in enhanced seroconversion towards all three TIV strains, compared to priming with placebo. Significant elevation of influenza-specific CMI was observed following immunization with M-001 alone.

Conclusions

The standalone and priming actions of M-001 were demonstrated in elderly participants despite the limitations of small population size and pre-existing HAI antibody titers in some participants. As a standalone vaccine, M-001 induced significant CMI to multiple strains and as a primer, M-001 enhanced HAI responses. Larger scale studies are warranted.

ClinicalTrials.gov registry number

NCT01419925.     

Evaluation of the safety,reactogenicity and immunogenicity of FluBlok trivalent recombinant baculovirus-expressed hemagglutinin influenza vaccine administered intramuscularly to healthy children aged 6–59 months

Background

Recombinant baculovirus-expressed hemagglutinin (rHA [FluBlok^®]) influenza vaccine is unique in avoiding production in eggs and its rapid production capability.

Objective

Compare the safety and immunogenicity of trivalent FluBlok to egg-grown trivalent influenza vaccine (TIV) in children.

Methods

Healthy children were randomized to receive two doses of study vaccines. TIV (7.5 μg HA/antigen), FluBlok-22.5 (22.5 μg rHA/antigen), or FluBlok-45 (45 μg rHA/antigen) were given to 115 children ages 6–35 months. TIV (15 μg HA/antigen) or FluBlok-45 was given to 41 children ages 36–59 months. Safety and reactogenicity data were collected post-vaccination. Serum hemagglutination-inhibition antibody (HI) titers were measured before and 28 days after vaccination.

Results

No serious vaccine-related adverse events occurred and reactogenicity events to equal volumes of TIV or FluBlok were generally similar. However, in the younger children, selected local and systemic symptoms were recorded significantly more frequently to 0.5 mL FluBlok-45 than to 0.25 mL doses of either the FluBlok-22.5 or 7.5 μg TIV vaccines. In the younger children, the immunogenicity to TIV was generally significantly superior to FluBlok. Serologic responses to FluBlok were higher in the older children than the younger group, but were still somewhat lower compared to TIV.

Conclusion

These data suggests that FluBlok is as safe but less immunogenic than similar volumes of TIV, particularly in the youngest children. The immunogenicity data is the converse of what has been observed in adults. Further studies examining the immunogenicity of FluBlok in older children are warranted.     

Fc functional antibody responses to adjuvanted versus unadjuvanted seasonal influenza vaccination in community-dwelling older adults

BackgroundSeasonal influenza vaccination with a standard trivalent influenza vaccine (TIV) induces a modest, and cross-reactive, Fc functional antibody response in older adults. Recent improvements to influenza vaccines include a quadrivalent influenza vaccine (QIV) and a TIV adjuvanted with the squalene-based oil-in-water emulsion MF59.MethodsPre- and post-vaccination serum samples from older adults vaccinated with QIV (n = 27) and adjuvanted TIV (n = 44) were studied using hemagglutination inhibition (HAI) assays and dimeric Fc-gamma receptor IIIa binding ELISAs, as a surrogate of antibody-dependent cellular cytotoxicity (ADCC).ResultsWe found that the unadjuvanted QIV elicited a stronger HAI response against the H1N1 vaccine virus than the adjuvanted TIV. Post-vaccination levels of HA-specific ADCC antibodies were similar for older adults vaccinated with QIV and adjuvanted TIV. The ADCC response to influenza vaccination was largely determined by pre-vaccination or baseline levels of these antibodies, with older adults with low baseline levels of ADCC activity demonstrating greater post-vaccination rises.ConclusionsIn this cohort of community-dwelling older adults, the QIV was at least as good as the adjuvanted TIV in the induction of ADCC and HAI responses. Further studies on how these antibody responses translate to efficacy in preventing influenza infections are warranted.     

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.     

General practice encounters following seasonal influenza vaccination as a proxy measure of early-onset adverse events

Background

In 2010, use of seasonal trivalent influenza vaccine (TIV) in children <5 years of age was suspended in Australia following reports of vaccine-related febrile convulsions. We investigated the utility of data on primary care [general practice (GP)] consultations for any reason within three days of receipt of influenza vaccine as recorded on the Australian Childhood Immunisation Register (ACIR) as a means of signal detection.

Methods

Data on GP consultations were obtained from Medicare Australia (Australian Government Department of Human Services) for children recorded on the ACIR as receiving either TIV or monovalent influenza vaccine. Rates of GP consultation by day following ACIR-recorded receipt of influenza vaccine were compared by year (2008–2010), vaccine type, age and region.

Results

In 2010, GP encounter rates on the day after receipt of the TIV manufactured by bioCSL (formerly CSL Biotherapies (Fluvax^®) were significantly higher than both bioCSL TIVs in the previous two years [rate ratio (RR) 1.9; 95% CI: 1.7–2.2] and Sanofi Pasteur TIV, Vaxigrip^® [RR 1.6, 95% CI 1.4–1.7] in 2009–2010. Encounter rates were also higher than for CSL Monovalent influenza vaccine, Panvax^® [RR 1.9, 95% CI 1.7–2.2] in 2009–2010. These findings were robust to adjustment for age group (≤2, >2 years) and region (Western Australia vs other Australian states/territories).

Conclusions

A primary care consultation on the day after vaccine receipt is a reasonable proxy for early reactogenicity and has potential for use in various settings.     

Dose sparing intradermal trivalent influenza (2010/2011) vaccination overcomes reduced immunogenicity of the 2009 H1N1 strain

Background

We hypothesized that low dose intradermal vaccination of the trivalent influenza vaccine (TIV) delivered by the MicronJet600™ (NanoPass Technologies, Israel) would be non-inferior to the full dose intramuscular and mid dose Intanza^® vaccination in the elderly and the chronically ill adults.

Methods

We performed a prospective randomized trial on elderly and chronically ill adults. Subjects were randomly assigned into 4 groups. Groups ID3 and ID9 received reduced dose ID TIV (3 μg and 9 μg of hemagglutinin (HA) per strain respectively) delivered by MicronJet600™ (NanoPass Technologies, Israel). Group INT9 received reduced dose ID TIV (9 μg) delivered by Becton Dickinson's Soluvia™ device (Intanza^®9, Sanofi-Pasteur, France). Control group IM15 received a full dose IM TIV (15 μg). We measured antibody titers by hemagglutination inhibition (HAI) and microneutralization (MN) assays at baseline and day 21.

Results

Baseline characteristics for all groups were similar (group and sample sizes: ID3 = 63; ID9 = 68; INT9 = 65; and IM15 = 66). At day 21 post vaccination, the GMT ratio and the seroconversion rates difference for all three strains of the ID vaccine groups were non-inferior to the IM vaccine group. The seroconversion rate, seroprotection rate, and the GMT of the H1N1 strains by HAI and MN assays were significantly higher in the ID groups compared with the full dose IM vaccine group. The seroconversion rates of the H3N2 strain by HAI assay were also significantly higher in the ID groups when compared with the full dose IM group. Direct comparison among the three ID groups showed no significant differences. No serious adverse events related to vaccination were reported.

Conclusion

Dose-sparing ID TIV can overcome reduced immunogenicity of the H1N1 strain, and according to some measures, for the H3N2 strain. At risk subjects indicated for the TIV should be considered for intradermal immunization to compensate for reduced immunogenicity.     

A randomized control trial comparing immunogenicity, safety, and preference for self- versus nurse-administered intradermal influenza vaccine

Background

Intradermally administered influenza vaccine is as immunogenic as intramuscular vaccine at a lower unit dose. New microinjection systems could allow self-administration of vaccine, potentially reducing the cost and inconvenience.

Objective

To compare the immunogenicity, reactogenicity, success rate, and acceptability of self- versus nurse-administered intradermal trivalent seasonal influenza vaccine.

Methods

Adults (18–59 years old) were randomized to either self- or nurse-administered intradermal vaccine. Prior to vaccination, participants completed a questionnaire and had blood drawn for hemagglutination inhibition titres. Participants in the nurse-administered group were vaccinated by study personnel. The self-administered group were given an instruction sheet and administered their own vaccine. All participants completed a questionnaire and adverse event diaries for 21 days post vaccination, at which time blood was again collected.

Results

Of the 228 participants, 115 were randomized to self-administration and 113 to nurse administration. Groups did not differ by sex, age, or levels of seroprotection at baseline. Of the 114 who completed self-administration, 106 (93%) were successful on the first attempt. There were no group differences in measures of immunogenicity for any of the strains. Self-administering participants reported a lower mean pain rating at vaccination but had larger areas of redness post-vaccination. Seventy percent of all participants said they would prefer intradermal over intramuscular vaccinations in the future, if given the choice.

Conclusion

Compared to nurse-administered intradermal influenza vaccine, self-administered vaccine was immunologically non-inferior and reached all EMA immunogenicity criteria for the A strains, was highly successful and well-accepted by study participants. Together, these data provide preliminary evidence of feasibility for this method of influenza vaccine administration, which may improve vaccine uptake in adults and increase efficiency of vaccine delivery during outbreaks.     

Intradermally-administered influenza virus vaccine is safe and immunogenic in healthy adults 18–64 years of age

Background

To increase vaccine acceptance, intradermal (ID) influenza vaccine (Fluzone^® Intradermal, Sanofi Pasteur Inc.) may be an attractive alternative to intramuscular (IM) vaccination due to smaller needle and volume injected.

Methods

A multicenter, randomized (2:1 ID vs IM vaccines) study, blinded for ID vaccine lots, was conducted among 4292 adults 18–64 years of age enrolled in October 2008. Three lots of investigational trivalent influenza vaccine containing 9 μg hemagglutinin (HA) per strain in 0.1 mL administered ID with a 30 gauge, 1.5 mm long needle were compared to standard dose vaccine (0.5 mL containing 15 μg HA/strain) given IM.

Results

The post-vaccination antibody geometric mean titers (GMT) for the ID vaccine were similar to the IM vaccine (H1N1: 193.2 vs. 178.3, H3N2: 246.7 vs. 230.7, and B: 102.5 vs. 126.9). Non-inferiority was met for the ID vaccine compared to IM vaccine as assessed by antibody GMT ratios (IM/ID) for all three virus strains (H1N1: 0.92, H3N2: 0.94, and B: 1.24). Seroconversion rates were non-inferior for H1N1 and H3N2, but not for B (ID vs. IM: H1N1: 61.2% vs. 60.5%, H3N2: 75.3% vs. 74.8%, and B: 46.2% vs. 54.2%). Seroprotection (HAI titer ≥1:40) rates were similar between groups (ID vs. IM, H1N1: 91.1% vs. 91.7%, H3N2: 90.7% vs. 91.4%, and B: 87.4% vs. 89.3%). Local injection site reactions overall were more common with ID than IM vaccine (ID vs. IM: 89.2% vs. 60.2%), but were usually grade 1 or 2 and transient. The frequencies of local injection site pain and systemic reactions were similar between vaccine groups, except more myalgia with IM vaccine.

Conclusions

The ID vaccine elicited immune responses comparable to IM vaccine except for the seroconversion rate to B virus. With the exception of pain, local injection site reactions were more common with the ID vaccine, but well-tolerated and of short duration.

Trial registration

ClinicalTrials.gov identifier: NCT00772109.     

Are immunosuppressive medications associated with decreased responses to routine immunizations? A systematic review

Background

Long-term immunosuppressive medications are being used more commonly for a variety of medical conditions, including immune-mediated diseases and organ transplantation. While these medications are often necessary, they are associated with an increased risk of serious infections. Vaccination may be a way to prevent a variety of infections but vaccine responses among patients receiving immunosuppressive therapies have been variable.

Purpose

To systematically review the literature describing immune responses among patients on immunosuppressive therapies to vaccinations including influenza, pneumococcal, meningococcal, hepatitis A and B, tetanus toxoid, pertussis, varicella, and zoster.

Data sources

English language citations in the MEDLINE and EMBASE databases from 1985 to 2010.

Study selection

Two reviewers independently screened titles and abstracts to identify prospective, controlled studies reporting pre- and post-vaccination titers of recommended vaccines in patients receiving long-term immunosuppressive therapies for full-text review.

Data extraction

Three reviewers independently assessed study characteristics including treatment regimens and pre- and post-vaccination titers.

Data synthesis

Of the 972 identified titles, fifteen met inclusion criteria. Ten studies assessed the effects of immunosuppressive medications on responses to influenza vaccine, four studies investigated responses following pneumococcal vaccination, and one study assessed both influenza and pneumococcal vaccination. Five of the studies that evaluated influenza vaccination showed partially diminished responses among individuals receiving immunosuppressive therapies, while one of the pneumococcal vaccine studies showed significantly decreased responses following vaccination. Patients treated with more than one immunosuppressive medication were the least likely to respond to vaccination.

Limitations

The heterogeneity of reported outcomes limits generalizeability.

Conclusions

Immunosuppressive therapy, particularly combination regimens, may blunt response to influenza and pneumococcal vaccinations. To ensure the best chance of response, immunizations should be administered prior to initiation of immunosuppressive medications whenever possible.     

Circulating pneumococcal specific plasma and memory B cells in the elderly two years after pneumococcal conjugate versus polysaccharide vaccination

Background

Polysaccharide conjugate vaccines prime for lasting memory responses in children and young adults. The potential value of these vaccines in the elderly is unclear.

Methods

We compared the frequency of circulating pneumococcal capsular polysaccharide (PPS) specific IgG, IgA and IgM plasma and memory cells by cultured ELISpot and supernatant screening two years after vaccination with the 7-valent pneumococcal conjugate vaccine (7vCRM) and/or the 23-valent pneumococcal polysaccharide vaccine (PPV) in 252 adults aged 50–80 years. Some individuals received a six-month boost with 7vCRM or PPV. PPS specific IgG memory detected two years post-primary vaccination was correlated with published matched serum IgG concentration pre- and up to one year post-primary vaccination.

Results

There was no difference by vaccine schedule in the quantity of plasma or memory cells detected. The concentration of in vitro PPS IgG produced by memory B cells isolated two years post-vaccination correlated with pre-vaccination serum IgG concentration and not with D28 post-vaccination responses regardless of vaccination schedule.

Conclusions

This study shows that circulating memory B cells numbers two years following immunisation with 7vCRM or PPV are best predicted by pre-vaccination serotype specific serum antibody concentration and not early post-vaccination serum antibody responses.     

An open-label, randomized, multi-center study of the immunogenicity and safety of DTaP-IPV (Kinrix™) co-administered with MMR vaccine with or without varicella vaccine in healthy pre-school age children

Background

In the US, it is recommended that 4-6 year old children receive diphtheria-tetanus-acellular pertussis (DTaP), inactivated poliovirus (IPV), measles-mumps-rubella (MMR), varicella (V), and influenza vaccines. Data relating to the concomitant administration of combination DTaP-IPV vaccine (Kinrix™; GlaxoSmithKline Biologicals) and influenza or V vaccines are currently limited. This study was undertaken to evaluate the immunogenicity and reactogenicity of Kinrix™ when co-administered with MMR (M-M-RII^®, Merck & Co.) and Varivax™ (Merck & Co.) in 4-6 year old children.

Methods

Phase IIIb, open-label, non-inferiority study (NCT00871117). We randomized (1:1) healthy 4-6 year olds to receive Kinrix™ + MMR + V on day 0 (Group 1), or Kinrix™ + MMR on day 0, followed by V at month 1 (Group 2). We measured DTaP-IPV immunogenicity before and 1 month post-vaccination (prior to V vaccination in Group 2). We collected local and general solicited symptoms within 4 days after vaccination and serious adverse events (SAEs) through 6 months post-vaccination.

Results

We enrolled 478 subjects. One month post-vaccination, >95% of subjects in both groups had booster responses to diphtheria, tetanus and pertussis antigens and all subjects had seroprotective anti-poliovirus antibody titers. Immune responses in Group 1 were non-inferior to Group 2 for responses to DTaP-IPV antigens according to pre-specified criteria. Reporting of solicited local events at the DTaP-IPV site appeared to be similar between the two vaccine groups, as was reporting of solicited general adverse events within 4 days of vaccination; no vaccine related SAEs were reported.

Conclusion

Concomitant administration of varicella vaccine with Kinrix™ and MMR did not impact the immunogenicity of diphtheria, tetanus, pertussis or poliovirus antigens. Both vaccine regimens were well tolerated. These results support the co-administration of DTaP-IPV, MMR, and V vaccines in 4-6-year-old children, providing protection against multiple diseases in a timely and efficient manner.     

Vaccination of adults 65 years of age and older with tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Boostrix(®)): results of two randomized trials

Background

Pertussis can cause significant morbidity in elderly patients, who can also transmit this disease to infants and young children. There is little data available on the use of acellular pertussis vaccines in recipients ≥65 years of age.

Methods

Two studies examined the safety and immunogenicity of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine (Boostrix^®) in healthy ≥65 year olds. In Study A subjects received single doses of Tdap and seasonal influenza vaccine either co-administered or given one month apart. In Study B subjects received either Tdap or tetanus-diphtheria (Td) vaccine. Antibodies were measured before and one month after vaccination. Reactogenicity and safety were actively assessed using diary cards.

Results

A total of 1104 subjects 65 years of age and older received a Tdap vaccination in the two studies. In study A, no differences in immune responses to Tdap or influenza vaccine were observed between co-administered or sequentially administered vaccines. In study B, Tdap was non-inferior to Td with respect to diphtheria and tetanus seroprotection, and anti-pertussis GMCs were non-inferior to those observed in infants following a 3-dose diphtheria, tetanus and acellular pertussis (DTaP) primary vaccination series, in whom efficacy against pertussis was demonstrated. Reports of adverse events were similar between Tdap and Td groups.

Conclusions

Tdap was found to be immunogenic in subjects ≥65 years, with a safety profile comparable to US-licensed Td vaccine. Tdap and influenza vaccine may be co-administered without compromise of either the reactogenicity or immunogenicity profiles of the two vaccines.     

A probiotic fermented dairy drink improves antibody response to influenza vaccination in the elderly in two randomised controlled trials

Background

Influenza vaccination is recommended for the elderly in many countries, but immune responses are weaker compared to younger adults.

Objective

To investigate the impact of daily consumption of a probiotic dairy drink on the immune response to influenza vaccination in an elderly population of healthy volunteers over 70 years of age.

Design

Two randomised, multicentre, double-blind, controlled studies were conducted during two vaccination seasons in 2005–2006 (pilot) and 2006–2007 (confirmatory). Eighty-six and 222 elderly volunteers consumed either a fermented dairy drink, containing the probiotic strain Lactobacillus casei DN-114 001 and yoghurt ferments (Actimel^®), or a non-fermented control dairy product twice daily for a period of 7 weeks (pilot) or 13 weeks (confirmatory). Vaccination occurred after 4 weeks of product consumption. Geometric mean antibody titres (GMT) against the 3 viral strains composing the vaccine (H1N1, H3N2, and B) were measured at several time intervals post-vaccination by haemagglutination inhibition test.

Results

In the pilot study, the influenza-specific antibody titres increased after vaccination, being consistently higher in the probiotic product group compared to the control group under product consumption. Similarly, in the confirmatory study, titres against the B strain increased significantly more in the probiotic group than in the control group at 3, 6 and 9 weeks post-vaccination under product consumption (p = 0.020). Significant differences in seroconversion between the groups by intended to treat analysis were still found 5 months after vaccination. Similar GMT results were observed for the H3N2 strain and H1N1 strain, confirming the results of the pilot study.

Conclusion

These studies demonstrate that daily consumption of this particular probiotic product increased relevant specific antibody responses to influenza vaccination in individuals of over 70 years of age and may therefore provide a health benefit in this population.     

A randomised, double-blind, non-inferiority clinical trial on the safety and immunogenicity of a tetanus, diphtheria and monocomponent acellular pertussis (TdaP) vaccine in comparison to a tetanus and diphtheria (Td) vaccine when given as booster vaccinations to healthy adults

Background

Increasing incidence of pertussis in adolescents and adults has stimulated the development of safe and immunogenic acellular pertussis vaccines for booster vaccination of adolescents and adults.

Purpose

To obtain clinical documentation of the safety and immunogenicity of a tetanus, diphtheria and monocomponent acellular pertussis combination vaccine (TdaP), when given as a booster vaccination to adults.

Methods

The trial was double-blind, controlled and randomised. 802 healthy adults, aged 18–55 years who had completed childhood vaccination with diphtheria, tetanus and whole cell pertussis vaccine (DTwP), were booster vaccinated with TdaP or Td. Blood samples were taken before and one month after the vaccination for serological analysis and adverse events were recorded during the one-month-follow-up period.

Results

The monocomponent acellular pertussis vaccine (aP) in the TdaP vaccine was immunogenic in adults with 92.0% of TdaP vaccinated subjects obtaining an anti-pertussis toxin (anti-PT) antibody booster response. TdaP was non-inferior to Td in eliciting seroprotective anti-tetanus and diphtheria antibody concentrations with more than 98% of subjects obtaining post-vaccination seroprotective concentrations (≥0.1 IU/mL). T and d booster response rates were 93.0% and 97.5%, respectively.The frequencies of solicited local adverse reactions were low and comparable between TdaP and Td vaccinees. In the TdaP group, 30.7% reported pain, 4.2% swelling and 2.0% erythema at the injection site. The most frequent solicited general symptoms were headache (20.4%), fatigue (17.0%) and myalgia (10.0%). In the Td group, 35.7% reported pain, 2.5% swelling and 3.2% erythema at the injection site, whereas headache, fatigue and myalgia were reported by 15.7%, 14.5% and 12.5%, respectively.In conclusion, TdaP Vaccine SSI was safe and immunogenic when given as a booster vaccination to adults. ClinicalTrials.gov registration number: NCT01033877.     

The effectiveness of influenza vaccination in preventing hospitalizations in children in Hong Kong, 2009–2013

Background

Influenza vaccination is widely recommended every year to protect individuals against influenza virus infection and illness. There are few published estimates of influenza vaccine effectiveness against hospitalization in children or from subtropical regions.

Methods

We conducted a test-negative year-round study between October 2009 and September 2013, recruiting children 6 months to 17 years of age admitted to two hospitals in Hong Kong with a febrile acute respiratory infection. Cases were tested for influenza A and B and conditional logistic regression was used to estimate vaccine effectiveness comparing influenza vaccination history of the trivalent influenza vaccine (TIV) among patients testing positive versus negative for influenza, adjusting for age and sex and matching by calendar week of recruitment.

Results

Overall vaccine effectiveness against hospitalization with laboratory-confirmed influenza A and B was estimated to be 61.7% (95% CI: 43.0%, 74.2%). The estimated vaccine effectiveness against A(H3N2) was 36.6% (95% CI: −25.5%, 67.9%) compared to 71.5% (95% CI: 39.4%, 86.6%) for A(H1N1)pdm09 and 68.8% (95% CI: 41.6%, 83.3%) for B.

Conclusions

Vaccine effectiveness against hospitalization in children varied from year to year, but was moderate to high overall even in an area with influenza activity throughout the year.     

Safety and immunogenicity of 2010-2011 H1N12009-containing trivalent inactivated influenza vaccine in children 12-59 months of age previously given AS03-adjuvanted H1N12009 pandemic vaccine: a PHAC/CIHR Influenza Research Network (PCIRN) study

Background

Concern arose in 2010 that reactogenicity, particularly febrile seizures, to influenza A/H1N1-containing 2010–2011 trivalent seasonal inactivated influenza vaccine (TIV) could occur in young children who had been previously immunized and/or infected with the pandemic strain. We conducted a pre-season study of 2010–2011 TIV safety and immunogenicity in children 12–59 months of age to inform public health decision making.

Methods

Children immunized with 1 or 2 doses of the pandemic vaccine, with or without the 2009–10 TIV, received 1 or 2 doses of 2010–11 TIV in an observational, multicentre Canadian study. Standard safety monitoring was enhanced by a telephone call at ∼24 h post-TIV when adverse events were expected to peak. Summary safety reports were rapidly reported to public health before the launch of public programs. TIV immunogenicity was assessed day 0, and 21 days after final vaccination. Clinical Trials Registration NCT01180621.

Results

Among 207 children, a general adverse event was reported by 60.9% of children post-dose one and by 58.3% post-dose two. Only severe fever (>38.5 °C) was more common in two-dose compared to one dose recipients (16.7%, n = 4 v. 1.0%, n = 2). At baseline 99.0% of participants had A/H1N1 hemagglutinin inhibition (HAI) titers ≥10, and 85.5% had a protective titer of ≥40 (95% CI 80.0, 90.0). Baseline geometric mean titers (GMT) were higher in recipients of a 2-dose schedule of pandemic vaccine compared to one-dose recipients: 153.1 (95% CI 126.2, 185.7) v. 78.8 ((58.1, 106.8, p < 0.001). At 21 days, all regulatory criteria for influenza vaccine immunogenicity were exceeded for A/H1N1 and H3N2, but responses to the B antigen were poor. No correlations between reactogenicity and either baseline high influenza titers or serologic response to revaccination were evident.

Conclusions

Infants and toddlers who received AS03-adjuvanted A/H1N1 2009 vaccine up to 11 months earlier retained high titers in the subsequent season but re-exposure to A/H1N1 2009 antigen in TIV resulted in no unusual adverse effects and 100% were sero-protected for A/H1N1 after receipt of the 2010–11 TIV.