1. 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 individual can take to prevent infection with influenza. The vaccines used against seasonal influenza have remained largely unchanged for many decades, consisting of three strains of influenza (trivalent 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 licensed quadrivalent influenza vaccines containing four strains of influenza (quadrivalent vaccines containing two influenza A strains and two influenza 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 possibility of adding an extra B component to the seasonal influenza vaccine.[1] This article briefly reviews the progress of quadrivalent influenza vaccines, as well as the rationale behind their introduction and an analysis of who is likely to benefit most by their introduction, using published articles, company websites, clinical trials websites, other websites and personal communication 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 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.[2] 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.[2] 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 vaccines (LAIVs) performing better in children aged 6 months to 7 years, with an overall efficacy of 83% (95% CI 69, 91).[3] However, there are only two licensed LAIVs, with FluMist® (MedImmune, 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. MedImmune’s LAIV 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 asthma, who wheeze, are immunocompromised or in close contact with people who are immunocompromised. 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, MedImmune’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 community.[4] In Japan, when all school children were given inactivated influenza vaccine between 1962 to 1977, Reichert et al.[5] estimated that the vaccination prevented approximately 37 000-49 000 excess deaths per year from all causes. In the elderly, there is also the added difficulty of overcoming underlying immune senescence[6] in order to achieve a satisfactory immune response following 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 susceptible to infection.[6]

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(H1N1) viruses, they have been composed of one A(H1N1) virus, one A(H3N2) virus and one B virus, reflecting the viruses that have circulated in the human population. These vaccines have been updated biannually 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.[7–12] This lineage first emerged in China in the mid 1970s but did not spread globally until the 1980s.[8,13] It was subsequently termed the B/Victoria/2/87 lineage and this lineage dominated globally for many years until the previous B lineage (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 particular country and the period examined.

Table I shows a summary of circulating influenza 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.[14] 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 dramatically from year to year. In Australia since 2000, the average percentage of circulating influenza 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 circulating 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 reveal 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 further 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 seasons.[10] This high proportion of poor/partial vaccine matches reflects our lack of understanding of what drives the predominance of one B lineage over the other, as well as the dynamics of co-circulation of B lineages, even though it is almost certainly a combination of virus drift, vaccine usage and falling 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 lineages will continue to co-circulate, something that also cannot be guaranteed, but, unlike 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[15]) for viruses to mix and re-emerge and subsequently infect humans.

Table I
figure Tab1

Circulation in Australia of influenza B virus lineages 2000–2011

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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 little prospect of any widespread benefit in the population arising from herd immunity following the introduction of quadrivalent vaccines. Therefore, the biggest benefit will be to those vaccinees who would have been at risk of infection when the vaccine they received was mismatched with the circulating B lineage 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.[16–21] Although influenza B also causes mortality across all age groups, deaths are disproportionately high in children aged up to 4 years.[22] 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 influenza viruses.[23] This is a similar proportion to that found in previous years in the US (34% of 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 B,[25] and influenza B paediatric deaths have also been described in New Zealand outbreaks.[26] 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.[27] A recent 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[28] 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 influenza based on their pre-existing medical conditions and, surprisingly, the deaths occurred very rapidly, with 70% of cases succumbing within 4 days from the onset of illness.[28] Including both lineages in the annual vaccine is also likely to improve 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 reactivity to the alternative lineage[29] when compared with adults who do show some low level of cross-lineage boosting following vaccination.[9,30] 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[31,32] and 31% in children given mismatched LAIV.[7]

5. Current Progress with Quadrivalent Influenza Vaccines by Manufacturers

Table II shows the current stage of development of quadrivalent vaccines at several major influenza 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 Federation of Pharmaceutical Manufacturers and Associations (IFPMA)[37] to influenza manufacturers. MedImmune (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.[38–40] Other manufacturers are in different stages of development with their quadrivalent inactivated influenza vaccines (QIV). GlaxoSmithKline (GSK) have completed their phase II and phase III studies on the safety, immunogenicity and efficacy in both children and adults and have submitted their QIV application for licensure in Europe and the US.[41–43] Sanofi Pasteur have completed phase II and phase III studies comparing their prototype QIV with their licensed TIV in children and adults, but are yet to submit an application for approval.[44–46] Novartis has also published phase II data comparing an adjuvanted TIV vaccine with a similar QIV vaccine containing their proprietary adjuvant MF59; however, it is not known if or by when they will develop or register a QIV without MF59.[47] It is also uncertain at this stage whether these QIVs, when they are introduced, will replace or supplement the existing TIVs.

Table II
figure Tab2

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

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6. Safety, Immunogenicity and Efficacy of 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 MedImmune’s Q/LAIV ‘FluMist®’ with the currently licensed T/LAIV in adults aged 18–49 years[48] and in children aged 2–17 years[49] 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 replicate in the host, which may decrease the immunogenicity 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.[48,49] 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 children aged 2–8 years of age after receiving one dose of Q/LAIV.[49]

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.[50] Similarly, Novartis compared their adjuvanted 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.[3] All three of these studies were designed to demonstrate non-inferiority of antibody responses 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 effectiveness data to be collected post-quadrivalent vaccine 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 effectiveness 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 estimated that during the 2001–8 seasons, a quadrivalent influenza vaccine in the US would have resulted in around 2.1 million fewer cases of influenza, 20 000 fewer hospitalizations and 1200 fewer deaths.[10,51]

7. Barriers to the Introduction of Quadrivalent 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.[10,11] However, since the avian influenza outbreaks of the mid 2000s, global influenza vaccine production has increased dramatically.[52] In 2006, global capacity was estimated to be 350 million doses of trivalent vaccine and, by 2010, this was predicted to grow to over 800 million doses,[52] which is likely to exceed the current market requirement for vaccine. A study by Reed et al.[53] modelled the impact on production that a QIV vaccine would have had between the 1999–2000 and 2008–9 influenza seasons in the US. They concluded that the theoretical number of QIV doses produced matched or exceeded the doses of TIV administered 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.[54] Adding to these vaccine doses from traditional 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,[55] insect cells[56] or bacteria.[57]

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 Recommendation procedure now gives a specific quadrivalent composition recommendation that lists representative viruses from both lineages at their biannual meetings,[58] a measure also endorsed by the WHO Strategic Advisory Group of Experts (SAGE).[59] 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 required. 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.[60]

Cost of vaccines is the one remaining factor that may affect the uptake of quadrivalent vaccines.[11] 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 coverage 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 effectiveness of seasonal influenza vaccine against circulating 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 circulate or if both lineages will co-circulate is limited. The adoption of quadrivalent vaccines will obviously 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 imperfect, is still the most cost-effective preventive method currently available.

8. Conclusion

Following the imminent introduction of quadrivalent 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. Other improvements are still eagerly awaited, such as influenza vaccines with an improved efficacy across all age groups and ultimately the holy grail of influenza protection, a universal influenza vaccine against all influenza A and influenza 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 recommended annual influenza vaccination.