Immunogenicity and safety of the Southern Hemisphere 2015 formulation of Vaxigrip®

ABSTRACT An inactivated split-virion trivalent influenza vaccine (IIV3; Vaxigrip®, Sanofi Pasteur) has been available globally since 1968. Here, we describe the results of an open-label, post-licensure trial (EudraCT no. 2014-005078-12) to confirm the immunogenicity and safety of the Southern Hemisphere 2015 formulation of IIV3. Adults 18–60 years of age and > 60 years of age (60 per age group) received a single 0.5-ml intramuscular injection of IIV3. Between baseline and day 21 after vaccination, hemagglutination inhibition (HAI) titers for each strain in IIV3 increased, on average, by at least 11-fold for younger adults and at least 5-fold for older adults. After vaccination, 89%–100% of the younger adult participants and 90%–98% of the older adult participants attained seroprotection (HAI titer ≥ 40) for each strain. Also, 66%–81% of younger adults and 45%–63% of older adults seroconverted or had a significant increase in HAI titer for each strain. For both age groups, these post-vaccination immune responses exceeded the criteria of the Committee for Human Medicinal Products former Note for Guidance for influenza vaccines. No serious adverse events were reported, and no new safety signals were detected. In conclusion, this study confirmed that the Southern Hemisphere 2015 formulation of IIV3 was well tolerated, highly immunogenic, and met the criteria for influenza vaccine efficacy and safety.

Since 1999, the Sistema Unico de Sa ude of Brazil has carried out annual influenza vaccine campaigns. 1 Target populations include children between 6 months and 5 years of age, adults 60 years of age, pregnant women, women within 45 days after giving birth, healthcare professionals, individuals with chronic respiratory diseases or with transplants, prisoners and people working in the correctional system, and the indigenous population. 2 The influenza vaccine has been provided free of charge, usually beginning in March or April, 1 which coincides with the beginning of the influenza season in the northern equatorial region. 3 Coverage of targeted populations in Brazil has been 60%-90%. 1,4 An inactivated split-virion trivalent influenza vaccine (IIV3; Vaxigrip Ò , Sanofi Pasteur) has been available globally since 1968 and in Brazil since 1984. 5 In compliance with World Health Organization recommendations for seasonal influenza vaccines, Vaxigrip contains hemagglutinin from two influenza A strains (H1N1 and H3N2) and one B strain. The vaccine has been shown to reduce the incidence of influenza infection, decrease workplace absenteeism, and decrease hospitalization and mortality in older adults and other at-risk populations. 6 Long-term experience has shown that the vaccine is well tolerated 7 and, compared with no vaccination, does not increase the rate of clinically important, medically attended events. 8,9 Here, we describe the results of an open-label, post-licensure trial (EudraCT no. 2014-005078-12) requested by the Brazilian health authorities (Agência Nacional de Vigilância Sanit aria), to confirm the immunogenicity and safety of the Southern Hemisphere 2015 formulation of IIV3. The vaccine was evaluated according to the European Medicine Agency's Committee for Medicinal Products for Human Use (CHMP) former Note for Guidance. 10 New guidelines became available in 2016, 11 after this study was completed.
The study was conducted at three sites in France and included 60 younger adults (18-60 years of age) and 60 older adults (> 60 years of age) to meet the minimum of 50 participants per group recommended in the former CHMP Note for Guidance (Table 1). In both age groups, approximately twothirds of the participants were female. Mean ages were 37.8 years in the younger adult group and 67.3 years in the older adult group. All participants, except for one younger adult who withdrew consent, received a single 0.5-ml intramuscular injection of the licensed 2015 Southern Hemisphere formulation of IIV3.
Between baseline and day 21 after vaccination, hemagglutination inhibition (HAI) titers for each strain in IIV3 increased by at least 11-fold for younger adults and at least 5-fold for older adults ( Table 2). After vaccination, 89%-100% of the younger adult participants and 90%-98% of the older adult participants attained seroprotection (HAI titer 40) for each strain. Also, 66%-81% of younger adults and 45%-63% of older adults seroconverted or had a significant increase in HAI titer for each strain. The lower immunogenicity in older adults was likely due to immunosenescence, 12 combined with a higher frequency of chronic medical conditions. Regardless, post-vaccination immune responses for each strain met the former CHMP criteria for both age groups.
As found in other studies of IIV3, 13,14 injection-site pain, myalgia, and headache were the most common solicited reactions in both age groups ( Table 3). Most of these solicited reactions were grade 1 or 2, and all were transient.
Unsolicited adverse events considered to be vaccine related but not recorded as solicited reactions were reported by two younger adults (one myalgia and one fatigue) and four older adults (two fatigue, one cough, and one sore muscles with fever), all of which were grade 1 or 2 and transient. No immediate adverse events (within 30 min of vaccination) or serious adverse events were reported. Thus, there were no new safety signals, and the vaccine was well tolerated. Although two-thirds of the participants in this study were women, which could have increased solicited reactions, 15,16 they remained within acceptable limits.
The results confirmed that the Southern Hemisphere 2015 formulation of IIV3 was well tolerated and highly immunogenic in adults and met the Brazilian regulatory authority's criteria for influenza vaccine efficacy and safety. Although the study was performed in France, the immunogenicity and tolerability of IIV3 is not expected to vary between populations and should be comparable in Brazilian adults.
In accordance with the former CHMP Note for Guidance, seroprotection was defined as a HAI titer 40. 10 However, the revised guidelines note a lack of robust evidence supporting a correlate of protection for influenza vaccines, and seroprotection no longer needs to be evaluated to support vaccine licensure. 11 Moreover, this historical threshold of seroprotection is losing favor as an estimate of protection. [17][18][19][20] Indeed, immunogenicity, although obviously essential, is only one of many factors determining the reallife effectiveness of influenza vaccines. This is one of the few reports describing the immunogenicity and safety of a Southern Hemisphere formulation of IIV3. Demonstration of the safety and high immunogenicity of IIV3 should help encourage its continued use in Brazil and other Southern Hemisphere countries.   Blood was collected before vaccination (day 0) and 21 days after vaccination. Serum HAI titers were measured in all vaccinated subjects with data available and as described previously. 21 HAI titers under the lower limit of quantitation (10) were assigned a value of 5 and all HAI titers above the upper limit of quantitation (10,240) were assigned a value of 10,240. To calculate GMTs, the means and 95% CIs were determined from log 10    Solicited reactions were collected by participants on diary cards for up to 7 days after the vaccination and were analyzed in all participants vaccinated. Erythema, swelling, induration, and ecchymosis were considered grade 1 for 25 to 50 mm, grade 2 for 51 to 100 mm, and grade 3 for > 100 mm. Fever was considered grade 1 for 38.0 C to 38.4 C, grade 2 for 38.5 C to 38.9 C, and grade 3 for 39.0 C. All other reactions were considered grade 1 for not interfering with activity, grade 2 for some interference with activity, and grade 3 for significant, preventing daily activity. Abbreviation: CHMP, Committee for Human Products for Medicinal Use. a Note for Guidance on Harmonization of Requirements for Influenza Vaccines, CPMP/BWP/214/96. 10