Quadrivalent influenza vaccine in the United States

Abstract

New strategies to improve influenza vaccines are ongoing. With the recent development of new vaccine formulations, such improvements have begun to materialize in formulations available to providers and their patients. One of the newest strategies developed has been to broaden the composition of the current influenza vaccine formulations from trivalent products to quadrivalent products. To date, three manufacturers have developed and tested four vaccine formulations for safety and immunogenicity. The growing availability of quadrivalent influenza vaccines is now a well-recognized advance among the growing opportunities to improve influenza prevention.

Influenza viruses circulate globally to cause human infection resulting in significant morbidity and mortality. Influenza infection in the United States is responsible for substantial medical and economic burdens, with estimated annual costs of $87 billion when accounting for lost productivity from missed work, hospitalizations, and lost lives.¹ Influenza-infected children younger than 5 y of age, alone, result in annual cost burden of $44 to $163 million for hospitalized children and $62 to $279 million for visits to hospital emergency rooms.² Between the 1976 and 2006 annual influenza-related deaths ranged between 3000 and 49 000 people.³

Epidemic human influenza infections can be caused by both influenza A and influenza B strains. Influenza A viruses are divided into subtypes based on the expressed surface antigens, hemagglutinin (HA) and neuraminidase (NA), while influenza B strains are divided into two genetically different lineages, Yamagata and Victoria. Influenza A/H1N1 was first recovered in 1933, 10 years before the first influenza B virus. As early as the 1940s, influenza B-Yamagata epidemics occurred every 2 to 4 y. By the 1980s, the influenza B-Victoria lineage emerged into global circulation, and was the predominant circulating strain from 1987–1989, followed again by Yamagata strain dominance in the 1990s.^4,5 Since 2001, both influenza B lineages have co-circulated annually contributing to 22–44% of influenza related pediatric mortality between 2004–2011, excluding the 2009–2010 influenza A H1N1 pandemic.^6-8

Annual influenza vaccine remains the primary method of influenza prevention. Antibodies to the HA antigen neutralize strain specific virus and protect against infection, while antibodies to the NA antigen reduce illness severity.⁹ Influenza viruses evade this strain specific immune response through the process of antigenic drift, where point mutations within the HA or NA genes result in decreased inhibition of the virus by pre-existing host circulating antibodies.⁹ Thus, antigenic drift plays a major role in the need for the reformulation of included vaccine strains from season to season.

Since the 1970s, influenza vaccines have been trivalent, containing an influenza A/H1N1 strain, an influenza A/H3N2 strain, and a single influenza B strain (either from the Yamagata lineage or the Victoria lineage). In the United States, the Vaccines and Related Biological Products Advisory Committee advise the Food and Drug Administration, with recommendations from the WHO, regarding the strains of influenza virus needed in the upcoming seasonal influenza vaccine. Part of the determination of vaccine composition involves predicting which one of the two influenza B lineages will be the predominant circulating strain going forward in time and therefore should be included in the vaccine, because immunity to an influenza B strain of one lineage does not confer protection to the alternate lineage.^8,10-12 It is important to note that only 50% of seasonal influenza vaccines between the 2001–2002 and the 2010–2011 influenza seasons contained the vaccine B strain lineage that matched the predominate circulating influenza B virus for that season. This frequent mismatch between vaccine strains and circulating influenza B viruses results in reduced vaccine efficacy and ultimately reduced community confidence in the influenza vaccine.

The burden of disease caused by influenza B strains from both lineages, the difficulty in predicting the lineage of the predominating influenza B virus in circulation for the upcoming season, and the lack of cross-protection between the viruses of both lineages support the inclusion of influenza B virus strains from both lineages in the seasonal influenza vaccine. Model analyses indicate that, depending on adequate vaccine supply, burden of influenza, and proportion of influenza B virus contributing to that burden annually, the introduction of quadrivalent influenza vaccine could result in improvement in influenza-associated outcomes.^3,12,13 Specifically, Reed and colleagues showed that the use of a quadrivalent influenza vaccine in the United States during influenza seasons between 2001 and 2008 would have resulted in ~2.7 million fewer cases of influenza, ~21 000 few hospitalizations, and ~1300 fewer deaths.¹³ The use of quadrivalent influenza vaccine should reduce mismatch between vaccine and circulating influenza strains and as a result, strengthen the community’s confidence in the annual influenza vaccine.

There are currently 4 quadrivalent influenza vaccines approved and available in the United States for the 2013–2014 influenza season: FluMist Quadrivalent (MedImmune), Fluarix Quadrivalent (GlaxoSmithKline), Fluzone Quadrivalent (Sanofi Pasteur), and FluLaval Quadrivalent (ID Biomedical Corporation of Quebec/GlaxoSmithKline). All quadrivalent influenza vaccines have been formulated to include a fourth influenza virus strain B/Brisbane/60/2008-like virus of the Victoria lineage, in addition to the strains found in the traditional trivalent influenza vaccines (A/California/7/2009 (H1N1)-like virus, a strain antigenically similar to A/Victoria/361/2011 (H3N2), and B/Massachusetts/2/2012-like virus of the Yamagata lineage).

Traditionally, influenza vaccines have been referred to as either TIV to indicate trivalent influenza vaccines or LAIV to indicate live attenuated influenza vaccines. Similarly, as quadrivalent influenza vaccines were being study in clinical vaccine trials, they were referred to as QIV or LAIV-Q. This nomenclature is used in the references provided herein, and in the detailed descriptions listed below, but it is important to highlight the new changes in influenza vaccine abbreviations since they have become the new standard beginning in 2013. TIV is now referred to as IIV3 for ‘inactivated influenza vaccine trivalent’. Likewise, QIV is now referred to as IIV4. LAIV is currently only manufactured as a quadrivalent vaccine so it can be referred to as LAIV or LAIV-4. Readers will note that cell culture based and recombinant influenza vaccines may also have the designated prefix to the standard for inactivated vaccine (ccIIV3 or RIV3 respectively). These two newer vaccine formulations are not yet marketed in quadrivalent formulations.

FluMist Quadrivalent (MedImmune)

FluMist Quadrivalent is the quadrivalent live attenuated influenza vaccine (LAIV) that will replace all trivalent LAIV for the 2013–2014 influenza season. FluMist Quadrivalent, administered in single-dose intra-nasal sprays, is approved for healthy, non-pregnant people aged 2 through 49 y. Randomized, double blinded, multicenter trials were performed to assess noninferiority of the immune response to quadrivalent LAIV when compared with trivalent LAIVs in children aged 2 through 17 as well as in adults aged 18 through 49 y. In both studies, immune responses to the quadrivalent LAIV were noninferior to the responses seen with trivalent LAIV. Furthermore, in children, quadrivalent LAIV induced a robust immune response to the influenza B strains of both lineages, while cross-reacting immune responses of trivalent LAIV to the alternating influenza B lineage strains were lower than responses to the strain included in the vaccine. The inclusion of the additional influenza B strain in the vaccine did not interfere with the immune response to the other strains in the vaccine.^14,15

The safety profile of quadrivalent LAIV was comparable to that of trivalent LAIV in both children and adults. In children aged 2 through 8 y, fever was more commonly reported in children who had received quadrivalent LAIV (5.4%) compared with those who received trivalent LAIV (3.1%). Also of note, the proportion of children who reported solicited symptoms was lower after receiving the second dose of vaccine than after the first dose.¹⁵ In adults, runny or stuffy nose was the most common solicited symptom.¹⁴ Adverse events (AE) were equally reported between the groups receiving quadrivalent or trivalent LAIV. The most common adverse events reported in the adult groups were sneezing, oropharyngeal pain, upper respiratory tract infection and cough, while vomiting was the most common AE reported in the children.^14,15

Fluarix Quadrivalent (GlaxoSmithKline)

Fluarix Quadrivalent is a quadrivalent inactivated influenza vaccine (QIV) that is available in addition to the trivalent inactivated influenza vaccine (TIV) during the 2013–2014 influenza season. Fluarix, administered as 0.5 mL intramuscular injection, is approved for people 3 y of age and older. Randomized multi-center studies were performed to assess noninferiority of immunologic responses of QIV vs. TIV in children ages 3 through 17 y and adults 18 y of age and older.^16,17 Both studies demonstrated that the immune responses to QIV were noninferior to the immune responses induced by TIV. QIV did elicit a more robust response than TIV to the alternate influenza B lineage for both adults and children. The addition of a second influenza B strain into the vaccine did not interfere with the immune responses to the other vaccine strains.^16,17

The safety and reactogenicity profile of QIV was comparable to TIV in both the adult and children. The most common solicited local reaction in both studies was pain at the injection site. The most common solicited general adverse events were drowsiness and irritability in children aged 3 through 5 y, and fatigue, headache, and muscle aches for children 6 y and older and adults. The most common unsolicited adverse event in both groups was nasopharyngitis.^16,17 Safety data were also presented in an open label subgroup of infants 6 mos to 35 mos of age. A phase 2 randomized controlled trial comparing trivalent Fluzone vaccine to quadrivalent Fluarix in infants 6 mos to 35 mos of age is being undertaken presently.

Fluzone Quadrivalent (Sanofi Pasteur)

Fluzone quadrivalent is a quadrivalent inactivated influenza vaccine (QIV) that will be available in addition to the trivalent inactivated influenza vaccine (TIV) during the 2013–2014 influenza season. Fluarix, administered as 0.25 mL intramuscular injection, is approved for children aged 6 through 35 mo and a dose of 0.5 mL for patients aged 3 y and older. Randomized controlled multi-center studies were performed to assess noninferiority of immunologic responses of QIV vs. TIV with each of the influenza B lineages in children ages 6 mo through 17 y and adults 18 y of age and older.^3,18 In both studies, the QIV-elicited immune responses were noninferior to those induced by the TIV. Antibody production to influenza B virus strains was higher in those who received QIV when compared with those who received TIV containing the alternate influenza B lineage.^3,18

The safety and reactogenicity profile of QIV was comparable to TIV in both the adult population as well as the children.^3,18 The most common solicited local reaction was pain at the site of injection. For children, the most common solicited general AE included irritability, abnormal crying, drowsiness, malaise, myalgia, decreased appetite, fever, and vomiting. For adults, the most common systemic symptoms were myalgias.^3,18

FluLaval Quadrivalent (ID Biomedical Corporation/GlaxoSmith/Kline)

FluLaval Quadrivalent is a quadrivalent inactivated influenza vaccine (QIV) that will be available in addition to the trivalent inactivated influenza vaccine (TIV) during the 2013–2014 influenza season. FluLaval Quadrivalent, administered as 0.5 mL intramuscular injection, is approved for people 3 y of age and older. Randomized controlled multicenter studies were performed to assess the noninferiority of immunologic responses of QIV vs. TIV with each of the influenza B lineages in children ages 3 through 17 y and adults 18 y of age and older.^3,10 In both studies, the QIV-elicited immune responses were noninferior to those induced by the TIV. Antibody production to influenza B virus strains was higher in those who received QIV when compared with those who received TIV containing the alternate influenza B lineage. The addition of a second influenza B strain did not interfere with the immune responses to the other strains in the vaccine.^3,10

Safety and reactogenicity profile were similar for QIV and for TIV in both the adult and the children studies. The most common local adverse effect was pain at the site of injection for all groups. The most common solicited systemic reactions in children aged 3–4 y included irritability, drowsiness, and decreased appetite; in children 5–17 y and adults over 18 y of age were muscle aches, fatigue, headache, and arthralgias.^3,10

The rationale for adding a second influenza B virus strain to the trivalent formulations of vaccine is clear. While availability for use during the 2013–2014 vaccination efforts is somewhat limited, future influenza vaccine seasons are likely to see widespread use. The new availability of quadrivalent influenza vaccines for the 2013–2014 influenza season is a step toward improving our public health armamentarium to reduce the predictable morbidity and mortality that comes every influenza season. While the clinical vaccine trials to date have centered on safety and immunogenicity of the quadrivalent influenza vaccine formulations, and predictive models support their use, the true public health impact following implementation awaits our experience.

10.4161/hv.27115