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The Coming Era of Quadrivalent Human Influenza Vaccines Who will Benefit?

Ian G. Ban and Lauren L. Jelley

WHO Collaborating Centre for Reference and Research on Influenza, Melbourne, VIC, Australia

Abstract influenza vaccines form the mainstay of public health and personal protection against infection with seasonal influenza viruses. These vaccines are designed to protect people against infection with the currently circulating influenza viruses. Since the late 1970s, this has required the use of a trivalent vaccine consisting of two influenza A viruses and one influenza B virus. However, since the early 2000s, a second lineage of B viruses has regularly circulated in many countries that is quite distinct, with only low levels of cross protection between the two lineages. Due to the difficulties in determining which B lineage will circulate, and matching this with the vaccine to be administered some 6-9 months later, there has been an increasing interest in the development of quadrivalent influenza vac- cines, containing two influenza B viruses representing both lineages. Develop- ment has been rapid and we are now on the cusp of a new generation of influenza vaccines becoming available. This paper discusses the issues and rationale behind this welcome development and who is likely to benefit most.

11. Background

Vaccination to reduce the burden of influenza is the major public health initiative in many countries as well as currently being the best measure an in- dividual can take to prevent infection with influ- enza. The vaccines used against seasonal influenza have remained largely unchanged for many de- cades, consisting of three strains of influenza (tri- valent vaccines containing two influenza A strains and one influenza B strain). However, in the next few years, perhaps as early as 2013, a significant advancement will occur, as at least two (possibly three) companies will make available their fully liceBsed quadrivalent influenza vaccines contain- ing four strains of influenza (quadrivalent vaccines con:aining two influenza A strains and two in- fluenza B strains). These changes follow on from a series of discussions that began at the 2007 US

FDA's Vaccines and Related Biological Products Advisory Committee (VRBPAC) about the pos- sibility of adding an extra B component to the seasonal influenza vaccine.''' This article briefly reviews the progress of quadrivalent influenza vaccines, as well as the rationale behind their in- troduction and an analysis of who is likely to beneflt most by their introduction, using pub- lished articles, company websites, clinical trials websites, other websites and personal commu- nication from company representatives.

2. Influenza Vaccines

Influenza vaccines differ from most childhood and adult vaccines as they are recommended for administration annually to a large range of both healthy and at-risk people. For example, in the

2178 Ban & Jelley

US, the Advisory Committee on Immunization Practices (ACIP) have since 2010 recommended that everyone older than 6 months should be vaccinated against influenza, with children aged 6 months to 8 years receiving two doses of the vaccine, 4 weeks apart, when receiving the vaccine for the first time.t^' The ACIP also recommended that people should be vaccinated annually as the composition of the vaccine may have changed, and if it had not changed then annual vaccination was still recommended on the basis that it will boost any existing antibody titres.'^' The need to revaccinate populations annually with influenza vaccines is driven by several factors, the main one being the modest efficacy of the non-adjuvanted trivalent inactivated influenza vaccines (TIVs). This was estimated in a recent meta-analysis to be only 59% (95% CI 51, 67) overall in adults aged 18-65 years with live attenuated influenza vac- cines (LAIVs) performing better in children aged 6 months to 7 years, with an overall efficacy of 83% (95% CI 69, 91).[31 However, there are only two licensed LAIVs, with FluMist® (Medlmmune, Gaithesburg, MD, USA) currently approved in the US, Canada, the EU, South Korea, Macao, Hong Kong, Israel, UAE and Mexico, and the Russian LAIV (RII, St Petersburg, Russia), both having a more limited age range (e.g. Medlmmune's LAFV is approved for use in individuals aged 2 through 49 years in the US, while the RII's LAIV is approved for children over 3 years in Russia) than TIV (6 months and over) and more contra-indications, e.g. it is not indicated for children who have asth- ma, who wheeze, are immunocompromised or in close contact with people who are immunocom- promised. As a consequence, LAIVs make up only a small proportion of global influenza vaccines (=2%), although this proportion is higher in the US (FluMist® will make up approximately 10% of the vaccine doses available for the 2012-3 season; 13 million out of 135 million projected doses) and are used mainly in children. However, Med- lmmune's LAIV has recently been adopted for use in British children and will be provided free of charge, in a bid to reduce influenza infections and their complications in children and the com- munity.I'*' In Japan, when all school children were given inactivated influenza vaccine between 1962

to 1977, Reichert et al.'^l estimated that the vac- cination prevented approximately 37000-49000 excess deaths per year from all causes. In the elderly, there is also the added difficulty of over- coming underlying immune senescence'^! in order to achieve a satisfactory immune response fol- lowing vaccination, and the problem seen in all age groups of waning immunity/antibody levels to influenza after relatively short periods of time (6-12 months) following vaccination, making them sus- ceptible to infection.'^

3. Influenza B: One Virus, Two Lineages

Today, the vast majority of influenza vaccines are egg-grown, detergent-spit, chemically inactivated influenza viruses (TIVs). Since 1978, following the re-introduction of seasonal A ( H I N I ) viruses, they have been composed of one A ( H I N I ) virus, one A(H3N2) virus and one B virus, reflecting the viruses that have circulated in the human pop- ulation. These vaccines have been updated bian- nually since 1998 based on the viruses circulating in both Northern and Southern Hemispheres, with at least one component being updated every year or two. This process has been complicated in the last 10 years by the emergence of an antigenically and genetically distinct lineage of influenza B viruses.t^"'^' This lineage first emerged in China in the mid 1970s but did not spread globally until the 1980s.'*''^' It was subsequently termed the B/Victoriay2/87 lineage and this lineage dominated globally for many years until the previous B line- age (now termed the B/Yamagata/16/88 lineage) re-emerged in the 1990s and again became the dominant lineage for over a decade. In 2002, the B/Victoria lineage returned once more and, since this time, these two B lineages have co-circulated in varying proportions depending on the partic- ular country and the period examined.

Table I shows a summary of circulating influ- enza in Australia over the period 2000-11 according to the samples received at the WHO Collaborating Centre for Reference and Research on Influenza in Melbourne, Australia.'''*' Both the proportion of influenza B viruses (of total influenza viruses) and the proportions of the two lineages are shown and, over this period, both have varied quite

Quadrivalent Influenza Vaccines 2179

Table I. Circulation in Australia of influenza B virus lineages 2000-2011

Year

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

%Bs

33.1

14.5

22.8

0.8

25.0

21.5

34.4

5.3

63.3

1.2

12.7

31.2

% B/Yamagata lineage

100

4.0

80.0

83.3

51.7

4.5

78.0

48.8

38.5

9.2

1.8

% B/Victoria lineage

96.0

20.0

16.7

48.3

95.5

22.0

51.2

61.5

90.8

98.2

Vaccine used in that year (lineage)

Yamagata

Victoria

Yamagata

Victoria

Yamagata

Victoria

Vaccine match to circulating B viruses

Complete

Low

Medium

High

Low

Medium

High

dramatically from year to year. In Australia since 2000, the average percentage of circulating influ- enz£ B viruses was 22.2%, with a range from 0.8% in 2003 to 63.3% in 2008. In most years, there was a lower proportion of influenza B viruses than influenza A viruses; however, in some years, such as 2008, influenza B viruses were the major cir- culating influenza type. Importantly, also in 2008, both B lineages co-circulated in almost equal proportions, meaning the influenza vaccine for that year provided coverage for less than half of the circulating B viruses. The Australian data re- veal poor matches with the recommended vaccine virus and the circulating B-lineage virus in 4 of the 12 years analysed, with a partial match in a fur- ther 3 years and a good match for the remaining 5 years. This finding is similar to the data from Europe and the US, where a vaccine mismatch for the B lineage occurred in four out of eight sea- sons.''"! This high proportion of poor/partial vac- cine matches reflects our lack of understanding of what drives the predominance of one B lineage over the other, as well as the djoiamics of co-circulation of B lineages, even though it is almost certainly a combination of virus drift, vaccine usage and falhng antibody levels to the alternative lineage, our attempts to reliably predict this with currently available data has proven elusive. This difficulty assumes of course that the two Uneages will con- tinus to co-circulate, something that also cannot be guaranteed, but, unhke influenza A viruses, there is

no animal reservoir for influenza B viruses (seals can carry influenza B but have not been shown to transmit to humans''^!) for viruses to mix and re- emerge and subsequently infect humans.

4. Who Will Benefit From Quadrivalent influenza Vaccines?

Given that the use of influenza vaccines in most countries is low and that, even in developed countries, coverage is unlikely to exceed 30% of the population, there is httle prospect of any widespread benefit in the population arising from herd immunity following the introduction of quad- rivalent vaccines. Therefore, the biggest benefit will be to those vaccinées who would have been at risk of infection when the vaccine they received was mismatched with the circulating B hneage or when both B lineages were co-circulating. While influenza B causes disease in all age groups, its incidence compared with influenza A is higher amongst older children and young adults.''^"^'^ Although influenza B also causes mortality across all age groups, deaths are disproportionately high in children aged up to 4 years.l̂ ^^ In the US in 2010-11,38% (44) of all influenza-related paediatric (defined as <18 years) deaths were due to influenza B, despite it being only 26% of the circulating in- fluenza viruses.I^^l This is a similar proportion to that found in previous years in the US (34% of

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2180 Barr & Jelley

paediatric deaths were associated with influenza B during 2004-8).[24] in Germany from 2005-8,25% of influenza-related paediatric (0-15 years) deaths were due to influenza Bp^ and influenza B pae- diatric deaths have also been described in New Zealand outbreaks.'^^' It was also reported in 2012 that influenza B outbreaks in Taiwan were associated with some 42 deaths compared with 12 deaths with influenza A involvement.'^^' A re- cent study of fatal influenza B cases involving both lineages (45 cases, of which 25 were typed as B/Victoria and 17 as B/Yamagata) in the US'^*' showed that these paediatric deaths were most commonly associated with myocardial injury, while in adults it was more commonly associated with concomitant bacterial infections, predominately Staphylococcus aureus. Interestingly, only 43% of the case patients with influenza B in this study were considered to be at high risk for severe in- fluenza based on their pre-existing medical con- ditions and, surprisingly, the deaths occurred very rapidly, with 70% of cases succumbing within 4 days from the onset of illness.'^^' Including both lineages in the annual vaccine is also likely to im- prove the response that children generate with subsequent immunizations, as children appear to accumulate natural immunity to influenza B more slowly than to influenza A and to generate very specific B-lineage responses, with little cross re- activity to the alternative lineage'^'' when com- pared with adults who do show some low level of

cross-lineage boosting following In randomized, placebo-controlled vaccine trials in younger adults, the vaccine efficacy against the opposite B lineage has been variable, ranging from 22% to 55% for TIV'^'-^^' and 31% in chil- dren given mismatched LAIV.'^'

5. Current Progress with Quadrivalent Influenza Vaccines by Manufacturers

Table II shows the current stage of development of quadrivalent vaccines at several major influ- enza vaccine manufacturers. These data were collected in May 2012 following an email request sent out by the Influenza Vaccines and Code Compliance section of the International Federa- tion of Pharmaceutical Manufacturers and Asso- ciations (IFPMA)'^'' to influenza manufacturers. Medlmmune (AstraZeneca) have developed and had licensed in the US, a quadrivalent vaccine (FluMist®) based on its LAIV for use in people aged 2-49 years.'̂ ^""*"' Other manufacturers are in different stages of development with their quad- rivalent inactivated influenza vaccines (QFV). Glaxo- SmithKline (GSK) have completed their phase II and phase III studies on the safety, immuno- genicity and efficacy in both children and adults and have submitted their QIV application for li- censure in Europe and the US.''*'""^' Sanofi Pas- teur have completed phase II and phase III studies comparing their prototype QIV with their li-

Table II. Company updates on their quadrivalent influenza vaccine development (only those responding to an email query are listed)

Company

Medlmmune

GlaxoSmithKline

Sanofi Pasteur

Green Cross Corp.

CSL Biotherapies

Vaccine type

Live attenuated

Inactivated

Inactivated, split virus

Inactivated

Coverage (age range)

2 ^ 9 y

3y and over

6 mo and over

Under consideration

5y and over

Stage of development

US FDA approved, 29 Feb 2012

Under assessment by US and EU authorities

VAXIGRIP® QIV IM: phase III ongoing; submission in 2013

Fluzone* QIV IM: submission in 2012

Pre-clinical evaluation

IM = intramuscular; NA==not applicable; QIV=quadrivalent inactivated vaccine.

Anticipated availability

2013-14 season in US

Not yet anrounced

2013

Reference

(331

(341

(351

1361

Ahn DH, personal communication

Cracknell B, personal communication

Quadrivalent Influenza Vaccines 2181

censed TIV in children and adults, but are yet to submit an application for approval.t'^'*^ Novartis has also published phase II data comparing an adjuvanted TIV vaccine with a similar QIV vac- cine containing their proprietary adjuvant MF59; however, it is not known if or by when they will develop or register a QIV without MF59.''*^1 It is also uncertain at this stage whether these QIVs, when they are introduced, will replace or sup- plement the existing TIVs.

6. Safety, immunogenicity and Efficacy cf Quadrivalent Vaccines

Quadrivalent vaccines are newly developed products and are required to meet regulatory standards for equivalent immunogenicity for the new component without adversely affecting the immunogenicity of the existing components and of course must be safe to use in all age groups for which it is intended to be used. A study comparing Medlmmune's Q/LAIV 'FluMist®' with the cur- rently licensed T/LAIV in adults aged 18-49 years''^! and in children aged 2-17 yearst"* ]̂ found that Q/LAIV was non-inferior to the current trivalent live attenuated vaccine, and that the seroresponse rates were similar. There was some concern that adding another virus to a live vaccine would lead to antigenically similar viruses competing to rep- licate in the host, which may decrease the immuno- genioity of the vaccine as a result, but it was found that the addition of a second virus was able to broaden the host's immunity against influenza B without affecting the immunogenicity of the other vaccine components.'''*-'*^' This may be because the two influenza B lineages are antigenically distinct and therefore not antagonistic. The safety of the Q/LAIV was found to be comparable across the groups, although fever was common in chil- dren aged 2-8 years of age after receiving one dose ofQ/LAIV.t"')

A study comparing Sanofi Pasteur's QIV in children aged 6 months-8 years found that the addition of an extra influenza B strain did not adversely affect safety or the immunogenicity of the vaccine.!'"' Similarly, Novartis compared their adJLvanted QIV with their adjuvanted TIV and found that the addition of another B strain did

not affect the immunogenicity or the safety of the vaccine.[2' All three of these studies were designed to demonstrate non-inferiority of antibody re- sponses to each influenza strain in QIV compared with responses to each respective strain in the TIV comparators and not to determine improved efficacy of the quadrivalent vaccine. It is not known if regulators will require vaccine effective- ness data to be collected post-quadrivalent vac- cine licensure, but this would seem unlikely given the size, complexity, cost and number of seasons over which these data may need to be collected. Clearly, improvement in influenza vaccine effec- tiveness with the additional B strain may vary considerably, from no difference when there is a good B-lineage match with the circulating B-lineage in TIV, to a small difference if both B lineages co-circulate, or even a larger difference in effectiveness if there was a mismatched B-lineage in the TIV vaccine. These differences may also be amplified in different age groups or when the circulation of influenza B is high. CDC have es- timated that during the 2001-8 seasons, a quad- rivalent influenza vaccine in the US would have resulted in around 2.1 million fewer cases of in- fluenza, 20000 fewer hospitaUzations and 1200 fewer deaths.^'"-'''

7. Barriers to the introduction of Quadrivaient influenza Vaccines

One of the main barriers that may have hindered the development of the quadrivalent vaccine in the past was the availability of sufficient vaccine production capacity to enable a fourth vaccine component to be added to the vaccine without a subsequent reduction in the available vaccine doses and hence a reduction in vaccine coverage.f'"'"' However, since the avian influenza outbreaks of the mid 2000s, global influenza vaccine production has increased dramatically.'^^' In 2006, global ca- pacity was estimated to be 350 million doses of trivalent vaccine and, by 2010, this was predicted to grow to over 800 milhon doses,'^^' which is likely to exceed the current market requirement for vaccine. A study by Reed et al.I'^' modelled the impact on production that a QIV vaccine would have had between the 1999-2000 and 2008-9 in-

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2182 Barr & ]elley

fluenza seasons in the US. They concluded that the theoretical number of QIV doses produced matched or exceeded the doses of TIV adminis- tered in most years. For the 2011-12 season in the US, some 132.1 million doses of TIV and LAIV were distributed and this figure is expected to rise to between 146 and 149 million doses for the 2012-13 season.'̂ '*' Adding to these vaccine doses from tra- ditional manufacturing facilities, will in the near future be vaccines produced by companies that do not use embryonated chickens eggs to produce their influenza vaccines and instead use systems such as plants,'^^' insect cells'̂ l̂ or bacteria.'^^'

Other quadrivalent vaccine production issues may arise due to the poor growth of one or both of the B viruses; however, this is less likely, as in recent years the WHO Influenza Vaccine Rec- ommendation procedure now gives a specific quadrivalent composition recommendation that lists representative viruses from both lineages at their biannual meetings,'^^' a measure also en- dorsed by the WHO Strategic Advisory Group of Experts (SAGE).f^'l This should allow for a more extensive selection, workup and optimization of B viruses from both lineages for inclusion in either the trivalent or quadrivalent vaccines as re- quired. An additional factor in reducing the issue of production/yield issues with QIV is the success in recent years of reassorting selected vaccine wild-type B viruses with high-yielding B viruses to produce B-reassortants for vaccine production that have enhanced growth and an increased yield of haemagglutinin protein, in a similar manner to what has been done with influenza A wild-type vaccine strains since the 1970s for TIVs.t^°i

Cost of vaccines is the one remaining factor that may affect the uptake of quadrivalent vac- cines.'"' A substantial increase in the cost of the quadrivalent formulation may reduce uptake by government-sponsored programmes and may result in the quadrivalent vaccine being targeted for certain age groups or target groups, e.g. the paediatric population or pregnant women, or the continued use of the cheaper trivalent vaccines, based on obtaining the broadest possible cover- age with influenza in the most cost-effective manner. If, on the other hand, the increased cost is marginal, then there is every chance that the quadrivalent

vaccine will replace the trivalent vaccine in all the age groups for which it is approved, given the high probability that it will improve the vaccine effec- tiveness of seasonal influenza vaccine against cir- culating influenza viruses, especially in children. While this is probably the situation for much of the developed world, it may take many years to extend through to the developing world, where some countries are only in the initial phases of either setting up their own production facilities or beginning the roll-out of imported influenza vaccine programmes and it may take a number of years to establish any influenza vaccination programme much less the inclusion of an extra B virus to the vaccine. Nevertheless, regardless of the time it takes to make quadrivalent vaccines available to the global population, it remains a worthwhile endeavour while there is co-circulation of two lineages of influenza B viruses and our capabilities to determine which lineage will circu- late or if both lineages will co-circulate is limited. The adoption of quadrivalent vaccines will ob- viously eliminate the chance of a complete vaccine B mismatch, which has occurred a number of times in the past decade; this should boost the public's confidence in the performance of the influenza vaccines, which, while it is likely to remain im- perfect, is still the most cost-effective preventive method currently available.

8. Conclusion

Following the imminent introduction of quad- rivalent influenza vaccines, it is not known how extensive the uptake and use of such a vaccine will be, as this will depend on many factors, including cost, regulatory authorities requirements, vaccine supply policies, funding issues and human health priorities. Regardless of when and where it is rolled out, the quadrivalent influenza vaccine represents another step forward in controlling infections caused by influenza B viruses, a virus that is often underestimated as a cause of significant morbidity and mortality, especially in the paediatric age group. Qther improvements are still eagerly await- ed, such as influenza vaccines with an improved efficacy across all age groups and ultimately the holy grail of influenza protection, a universal

Quadrivalent Influenza Vaccines 2183

influenza vaccine against all influenza A and in- fluenza B viruses that has long-term protection for all age groups, as well as having a minimal number of doses (e.g. two initial doses followed by boosters every 5-10 years), rather than the currently rec- ommended annual influenza vaccination.

Acknowledgements

The authors would like to thank Dr Heath Kelly for his critical reading and helpful suggestions in the preparation of this manuscript.

The Melbourne WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health and Ageing. The Mel- bourne WHO Collaborating Centre for Reference and Re- search on Influenza has received funding from influenza manufacturing companies and the IFPMA to conduct certain agreed projects. Ian G. Barr holds a small number of shares in a company that manufactures influenza vaccines.

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Correspondence: Dr Ian Barr, WHO Collaborating Centre for Reference and Research on Influenza, VIDRL, 10 Wreckyn Street, North Melbourne, VIC 3106, AustraUa. E-mail: Ian.Barr@ir\fluen2acentre.org

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