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Influenza vaccines: from whole virus preparations to recombinant protein technology Expert Rev. Vaccines 13(1), 31–42 (2014)

Victor C Huber Division of Basic Biomedical Sciences, University of South Dakota, 414 E Clark Street, Vermillion, SD 57069, USA Author for correspondence: Tel.: +1 605 677 5163 Fax: +1 605 677 6381 [email protected]

Vaccination against influenza represents our most effective form of prevention. Historical approaches toward vaccine creation and production have yielded highly effective vaccines that are safe and immunogenic. Despite their effectiveness, these historical approaches do not allow for the incorporation of changes into the vaccine in a timely manner. In 2013, a recombinant protein-based vaccine that induces immunity toward the influenza virus hemagglutinin was approved for use in the USA. This vaccine represents the first approved vaccine formulation that does not require an influenza virus intermediate for production. This review presents a brief history of influenza vaccines, with insight into the potential future application of vaccines generated using recombinant technology. KEYWORDS: hemagglutinin • influenza • recombinant protein • vaccine history

Influenza viruses are members of the Orthomyxoviridae family, and they cause acute respiratory infections that are associated with 3– 5 million hospitalizations and 250– 500,000 deaths worldwide on an annual basis [1]. Although multiple aspects of host immunity contribute to clearance of this virus, natural infection is associated with increased titers of serum antibodies directed at the variable, globular head of the viral hemagglutinin (HA) [2,3]. Based on this observation, vaccines that mimic this response to natural virus exposure have been developed [4]. Specifically, since 1945, vaccines against influenza viruses have been available as either inactivated influenza virus (IIV) [5] or live attenuated influenza virus (LAIV) preparations [6]. Both of these vaccine preparations rely on influenza virus intermediates during the vaccine production cycle [7]. Recent development efforts have utilized vaccine platforms that do not rely on viral intermediates to induce anti-HA antibodies. These include both DNA [8] and recombinant protein [9] vaccine preparations. In January 2013, the US FDA licensed FluBlok (Protein Sciences Corp., Meriden, CT, USA) as the first approved influenza vaccine that is generated without propagation of whole influenza www.expert-reviews.com

10.1586/14760584.2014.852476

virus during production. This vaccine consists of a recombinant HA (rHA) preparation that can induce immunity that mimics the anti-HA response observed after vaccination with IIV and LAIV preparations [10], and this vaccine has demonstrated efficacy and effectiveness in clinical trials [9,11,12]. This review will discuss the history of influenza vaccines from the initial, whole virus preparations through FluBlok approval, including a discussion of recent efforts to target non-HA influenza virus epitopes. These new approaches toward vaccine design and production have the potential to yield vaccines that are produced more rapidly, as we move toward improved vaccines that prevent both seasonal and pandemic influenza virus infections. Influenza virus

The infection cycle of influenza virus is initiated by interactions between the viral HA glycoprotein and sialic acid residues on host cell proteins [13]. The genome of influenza A virus is contained on eight individual, negative-sense RNA segments that express the proteins required for virus propagation within host cells [14]. These include structural proteins, polymerase proteins and nonstructural proteins [15].

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known as antigenic shift [35]. This drastic change in genes allows the virus to infect a 2009 large, naı¨ve population that has no preH1N1 (A and A′) H1N1 H1N1 existing immunity toward this new influenza A virus subtype. Once these viruses H2N2 establish stable transmission within the human population, they undergo a continH3N2 uous seasonal change in the HA expressed, known as antigenic drift, which is typically minor compared with the changes associInfluenza B virus ated with a pandemic [36]. Evaluation of the genetic composition of all pandemic Notable near pandemics and pandemic threats 1947: Emergence of A′ variant of H1N1 influenza viruses isolated, to date, indicates 1976: Fort Dix H1N1 influenza outbreak that adaptation of these viruses occurs 1997 and 2003–present: H5N1 within a mammalian species prior to sus1999: H9N2 tained human-to-human transmission [37]. 2003: H7N7 2013–present: H7N9 Pigs are the most frequently cited intermediate species for this gene Figure 1. Influenza pandemics of the 20th and 21st century. Information regarding exchange [34,38], although humans can conpandemics and near pandemics of the 20th century are derived from Kilbourne. tribute to this phenomenon [39]. As an Data taken from [42]. example, the 2009 H1N1 pandemic virus circulated as a triple reassortant contained During this infection cycle, the HA, neuraminidase (NA) and genes derived from influenza viruses that infected human, avian the M2 ion channel proteins are expressed at the host cell sur- and swine species [40]. face [15]. An M1 matrix protein surrounds the viral RNA genome, and nascent, enveloped viral particles bud from the host cell [16]. Influenza pandemics It should be noted that influenza viruses express their HA as a The most devastating influenza virus pandemic on record was single molecule, known as HA0, which is subsequently cleaved the 1918 ‘Spanish influenza’ pandemic (FIGURE 1), which was into HA1 and HA2 subunits at a basic cleavage site [17]. The associated with 40 million deaths worldwide [41]. Although not dominant protein expressed on the virion is the HA glycopro- classified as H1N1 at the time, the dominant influenza A tein [18], followed by the NA glycoprotein [19] and the M2 ion viruses that circulated in humans from 1918 through 1956 are channel [20]. Based on the accessibility of these three proteins dur- believed to have been variants within the H1N1 subtype [42,43]. ing the infection cycle, all three have been evaluated as In 1957, the circulating H1N1 subtype was replaced by the vaccine targets. H2N2 subtype influenza A virus, initially referred to as Three types of influenza virus are known to circulate within A2 [44,45], and this ‘Asian influenza’ pandemic was associated humans, influenza A, influenza B and influenza C [21]. Based with approximately 2 million deaths worldwide [41]. Following on their ability to circulate within different species, including the 1957 pandemic, vaccines were reformulated to include a chickens, pigs and humans, influenza A viruses represent the representative H2N2 isolate [46]. This shift in HA expression most significant pandemic threat. There are 16 different HAs represented the first antigenic shift on record, although subseand 9 different NAs within the influenza A virus type, which quent evaluation of pre-1918 post-infection sera indicated that have been found in the avian population [22,23]. An influenza H2N2 circulated in humans prior to the virus that expresses a 17th HA, designated H17, has been iso- 1918 H1N1 pandemic, and was the likely cause of the 1889– lated from bats, but has not been found to date in any other 1890 influenza pandemic [47]. This was the first evidence of the species [24]. The influenza A viruses that circulate within birds influenza HA recycling within the human population [48]. Simitypically exist within the gastrointestinal tract [25,26] and do not lar to the 1957 pandemic, the 1968 ‘Hong Kong influenza’ frequently infect humans [27,28]. When these viruses directly pandemic demonstrated an antigenic shift from influenza A infect humans, they do not typically have the characteristics viruses of the H2N2 subtype to those of the associated with human-to-human transmission [29,30]. However, H3N2 subtype [49,50]. Approximately 1 million people died when these viruses acquire the appropriate genetic material that worldwide in association with this virus [41], which represented allows for human-to-human transmission, they have the poten- the last true pandemic of the 20th century [42]. tial to cause a pandemic. Acquisition of the genetic requireAlthough not typically classified as a true pandemic, the ments for effective transmission can be either through point ‘Russian Flu’ age-restricted pandemic occurred in 1977 [42], mutation [31,32] or reassortment within a ‘mixing vessel’ [33,34]. shortly after the ‘swine flu’ scare of 1976 [51], and represented A frequent characteristic of pandemic influenza A viruses is the the re-introduction of the H1N1 influenza A subtype into the abrupt, sudden change of the HA from one subtype to another, human population. The virus that emerged was antigenically 1918

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similar to the H1N1 virus that circulated in the 1950s [52,53], and unlike prior influenza A virus pandemics, the H1N1 did not replace the H3N2 virus in the human population [54]. The emergence of this virus in 1977 was a significant event in the history of influenza virus circulation as variants within these two influenza A virus subtypes have co-circulated in humans into the present day [55]. After 1968, the next influenza virus to receive a pandemic classification was the triple assortment H1N1 virus that emerged in 2009 [56], which was associated with an estimated 284,500 deaths worldwide during the first 12 months of circulation [57]. The first cases of the 2009 H1N1 pandemic influenza virus were reported in April 2009 [58], and a monovalent vaccine against this virus was available by October 2009 [56]. The H1N1 virus that began circulating was antigenically more similar to the viruses that infected humans in 1918 and 1976 [59,60] than the H1N1 viruses that circulated in 2008 [61,62], demonstrating another potential recycling event for an HA expressed by influenza A viruses. Also, unlike typical, seasonal influenza viruses, this pandemic H1N1 virus circulated throughout the summer months and was not restricted to circulation in the winter [56,63]. Current influenza viruses that remain on our pandemic radar include those of the H5N1 [64], H7N7 [65,66], H7N9 [67] and the H9N2 [68] influenza A virus subtypes. All of these viruses have infected humans in recent years, many with high mortality rates [69], but none of these have demonstrated the ability to establish sustained human-tohuman transmission. Vaccination to limit influenza virus epidemics & pandemics

The 1918 influenza virus pandemic occurred prior to isolation of influenza viruses, and it also occurred in the pre-antibiotic era [70]. Since the majority of influenza virus-associated deaths during this pandemic were due to secondary bacterial infections [71], bacteria were the target for vaccine-induced prevention of death during the 1918 pandemic [72,73]. Once influenza A viruses were isolated in 1933 [74] and influenza B viruses were isolated in1940 [75], vaccines could be developed toward these viral agents. By 1945, inactivated virus vaccines against influenza A virus and influenza B virus were available [76,77]. The first major reformulation of these vaccines was initiated after the 1947 pseudopandemic [42], which was defined by the emergence of an A´ variant of the H1N1 influenza virus [42,78,79]. This experience demonstrated the first complete failure of influenza vaccines [80]. Specifically, since this A´ virus (A/Fort Monmouth/1/47, FM47) represented a significant change from the A virus that was included in the vaccine (A/ Puerto Rico/8/34, PR8), the available vaccine was immunogenic toward PR8, but this vaccine-induced immunity did not prevent infection with the FM47 virus that circulated [81,82]. Interestingly, it was quickly realized that routine influenza virus surveillance during this period actually detected the antigenically distinct A´ variant virus, and the conclusion was that with appropriate foresight, a representative A´ isolate could have www.expert-reviews.com

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been included in the vaccine [81–83]. This significant observation served as the impetus for the WHO to establish an influenza virus surveillance network to identify current circulating strains and select viruses for inclusion in future vaccines. The establishment of this surveillance network is documented in a WHO bulletin from 1953, with a description of the justification and role of this surveillance network [83]. Some influenza vaccine formulations that followed, including those produced commercially, were prepared as polyvalent preparations that contained as many previously circulating influenza strains as possible. For example, a commercial polyvalent vaccine that was produced in the 1960s contained the following virus isolates: A2/Japan/170/62, A2/Taiwan/1/64, A/PR/8/34, A1/Ann Arbor/1/57 and B/Mass/3/66 [84]. As the 1957 and 1968 pandemic viruses, and their subsequent drift variants emerged, recommendations were made to vaccinate only against current and future antigenic variants, rather than continuing to generate vaccines containing noncirculating variants [48]. In 1977, the re-emergence of the H1N1 subtype prompted the initial use of a monovalent vaccine developed toward the A/New Jersey/1/76 virus [85], and eventually the creation of a bivalent influenza vaccine preparation that contained two influenza A isolates (H1N1 and H3N2) and a separate influenza B virus vaccine [86,87]. This eventually led to trivalent influenza vaccine preparations [88] that were generated similar to the ones in use today [89]. This approach toward limiting the spread of a potential pandemic virus through implementation of a monovalent vaccine was repeated in 2009 with the pandemic influenza vaccine that contained the A/California/4/09 (H1N1) (CA09) influenza isolate [90]. This pandemic influenza vaccine was recommended in addition to the trivalent, seasonal influenza vaccine administered during the 2009 influenza season [91,92]. Ultimately, in the subsequent 2010 reformulation of the trivalent, seasonal influenza vaccine, the prepandemic H1N1 isolate included in previous formulations (A/Brisbane/ 59/07 [H1N1]) was replaced with the pandemic CA09 virus isolate [93–95]. Vaccine formulation

With regard to the types of vaccine preparations available, the earliest vaccines developed against influenza viruses were composed of IIV preparations [76,77], and these were first licensed for use in the USA in 1945 [96]. Improvements in IIV formulation in the 1960s were implemented in an effort to minimize reactogenicity, specifically in children [97]. These changes resulted in a vaccine composed of inactivated whole viruses that are currently delivered as either split or subunit preparations [7]. Alternatively, LAIV vaccine preparations, containing mutations that conferred temperature sensitivity, attenuation and cold adaptation, were initially developed in the 1960s [98], but were not licensed for use in the USA until 2003 [6]. It is worth noting that LAIV preparations were introduced in Russia in the 1980s and have been used routinely since that time [99,100]. Regardless of the formulation, vaccination is known to mimic natural infection with regard to its ability to induce HA-specific 33

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antibodies that can be detected in serum [101–103]. As one would expect, delivery of LAIV, which is via the natural, respiratory route, has demonstrated the ability to induce antibodies within the upper respiratory tract, but the presence of these antibodies is not always detected [104]. The most frequently mutated protein within the influenza A virus subtype is the HA molecule [105], which is believed to incorporate genetic changes that allow the variant viruses to escape host immunity toward the globular head of the HA [106]. The immunity toward this globular head of the HA can be acquired through either infection or vaccination, and a virus that can successfully evade this immunity can spread to multiple individuals that do not have immunity toward this drift variant. To date, IIV and LAIV vaccine formulations remain the most widely used forms of vaccination against the influenza virus [107] and both require propagation of infectious influenza virus in eggs as part of the production cycle [7]. This production cycle can take 6–9 months from selection of vaccine components through delivery of vaccine to the population [7], due in part to the multiple steps involved in the process. Vaccine production

Since 1969, approaches to produce influenza A virus vaccines have included the use of the master donor virus (MDV) derived from the A/Puerto Rico/8/34(H1N1) (PR8) influenza A virus isolate that has a high propagation phenotype in eggs [108]. Creation of annual influenza vaccines using this approach relies on the natural reassortment properties of influenza A viruses and uses 10-day-old fertilized chicken eggs [35]. Reassortment strategies are designed to generate viruses that express the two common circulating HA and NA proteins along with six genes from the MDV. There are 256 unique reassortant viruses that can emerge from two viruses injected into eggs simultaneously [109], and the process associated with selection of reassortants that contain this 2:6 ratio of humanto-MDV influenza virus genes contributes to the 6–9 month production cycle for influenza vaccines [35]. To aid in this process, antibodies directed toward the PR8 HA and NA can be included to reduce the likelihood that these two surface proteins will be expressed after reassortment [110,111]. The MDV used for the influenza A virus component of LAIV vaccines in the USA is derived from the A/Ann Arbor/6/60(H2N2) isolate, whereas the MDV for the influenza B virus component of LAIV vaccines is derived from the B/Ann Arbor/1/66 [112–114]. Alternatively, in Russia, the MDV for the influenza A virus component of LAIV vaccines is derived from the A/Leningrad/ 134/57(H2N2) isolate, whereas the MDV for the influenza B virus component of LAIV vaccines is derived from the B/ USSR/60/69 virus isolate [99,100]. At this time, an MDV for IIV production of influenza B virus vaccines is not available, rather a high-growth variant that represents the dominant influenza B virus isolate is selected annually for propagation in eggs [115]. Reassortment of the selected circulating strain with the appropriate MDV yields seed stocks of virus that can be used for vaccine production. In addition to the length of time associated with creation of seed stocks, the multiple steps of 34

inactivation required for IIV preparations [7] and subsequent quality control can delay the delivery of vaccine doses [116]. Furthermore, this process requires a readily available stock of eggs, and it has been previously noted that this may not be present if the pandemic comes from an avian species that is also being affected by the virus [117]. One recent advance that has been implemented to improve the propagation of influenza viruses for vaccine production involves the use of tissue culture cells, specifically Madin–Darby canine kidney cells [118]. Preparations of Madin–Darby canine kidney cell-based influenza vaccines were first approved in Europe in 2007 (Novartis’ OptiFlu vaccine) and received FDA approval in the USA in November of 2012 (Novartis’ Flucelvax vaccine). These cell-based vaccines alleviate the egg requirement, which can reduce the time required to complete the vaccine production cycle [119,120]. As an added benefit, this cell-based approach also allows individuals with egg hypersensitivities, who are unable to receive egg-based vaccines, to be vaccinated against influenza viruses [121]. LAIV vaccine preparations can be more rapidly delivered to patients, whereas IIV preparations must be inactivated prior to vaccination. Inactivation of influenza vaccines can be achieved using either formalin or b-propiolactone treatment [122,123]. The splitting of surface antigens is typically achieved by treatment with a detergent like Triton X-100 [124,125] and these split antigens can be further purified for subunit preparations [126,127]. Influenza vaccines that specifically target HA

Since the major focus of humoral immunity during a natural infection is the HA, inducing antibodies against this protein is the ultimate goal of all approved vaccine approaches. Recent advances in molecular approaches toward modulating gene expression have allowed for the development of a number of different vaccine vehicles that can be used to generate immunity toward the HA. Here we will discuss recombinant DNA (rDNA) and recombinant protein (rHA) approaches that have been developed to directly induce immunity toward influenza virus HA. In addition to the approaches discussed here, there have been a number of viral vector-based approaches that induce immunity toward the HA, but discussion of these approaches is beyond the scope of the current review. It should be noted that some of these viral vector-based vaccines have been evaluated clinically [128,129], with many others in development that may eventually progress toward clinical approval [130]. Gene transfer and expression of protein from rDNA was first demonstrated in vivo by Wolff et al. [131]. An advantage to rDNA vaccines includes the ability to rapidly modify and mass-produce the plasmid DNA in an effort to keep up with the constant changes that occur within the influenza HA [132–135]. Since this approach does not require the use of a viral intermediate at any point in the production process, it is readily adaptable to new HA variants and has demonstrated safety in humans [8,136]. Unfortunately, while safe, the responses to rDNA vaccines have not been as robust in humans as they have been in small animal models [137], Expert Rev. Vaccines 13(1), (2014)

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limiting the translation of this vaccine approach into the clinical setting. More recent human trials using this approach have yielded more favorable results [138,139], so the potential application of rDNA technology toward future influenza vaccines remains. As an alternative to rDNA inoculation, creation of rHA from rDNA constructs allows for the rapid manipulation and production of a protein of interest [140,141], with demonstrated immunogenicity and safety in humans [11]. Using the HA protein as a target, a recombinant vaccine against influenza virus, known as FluBlok, was approved for use by the FDA in January of 2013. This is not the only rHA vaccine that has been tested in clinical trials, but it is the first to achieve FDA approval. Other rHA preparations in clinical trials include bacterialexpressed HA1 preparations [142,143], like the one being developed by Vaxinnate (Cranbury, NJ, USA). Recombinant vaccines that target influenza HA

The FluBlok vaccine is a recombinant protein-based vaccine that induces immunity toward the influenza virus HA protein. The FluBlok vaccine technology uses on an insect virus (baculovirus) to express the influenza HA as an uncleaved HA0 (rHA0) in the Spodoptera frugiperda insect cell known as Sf9 [144]. Serum-free conditions are used to express this rHA0, which is subsequently removed from the cell surface and purified using column chromatography and ultrafiltration [145]. Initial studies with the FluBlok vaccine technology included the testing of preparations of rHA0 proteins in mice, with emphasis on HA proteins from H3 influenza viruses [146] and the potential need for an adjuvant [147]. These vaccines in murine models demonstrated strong immunogenicity that protected against challenge with influenza viruses, and in many cases, an adjuvant was not needed to achieve optimal immunity [148] . Vaccines based on rHA0 were first tested clinically (Phase I) in 1995 [10]. This trial included rHA0 from the H3 subtype and a group that received Alum as an adjuvant. Using percent seroconversion (‡fourfold increase in titer compared to prevaccine sera), this initial clinical trial demonstrated vaccine efficacy as defined using HA inhibition (HAI), ELISA and neutralization assays. Furthermore, there was no evidence that inclusion of Alum as an adjuvant improved overall immunogenicity [10]. Based on this finding, current formulations of FluBlok are prepared without adjuvant [9]. Subsequent trials with rHA0 from a single subtype demonstrated similar efficacy, including vaccines that incorporated the HA from H5 influenza viruses [149]. When FluBlokTM was prepared as a trivalent influenza vaccine that is similar to the vaccines prepared for seasonal influenza virus circulation (H1N1, H3N2 and B), seroconversion was demonstrated for all three vaccine components in two independent trials [150,151]. In 2013, FluBlok was approved for delivery to adults aged 18–49 years by the FDA in the USA. During clinical trials, the majority of adverse events following rHA0 delivery to healthy adults were most frequently associated with pain at the injection site [9–11]. Current IIV vaccine preparations include 15 mg HA content for each influenza strain included (45 mg total HA content for the trivalent vaccines and 60 mg total HA content for the www.expert-reviews.com

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recent quadrivalent vaccines), without evidence of consistent reactogenicity in vaccine recipients [152,153]. Escalation of HA content to 90 mg was required to achieve moderate seronconversion in some clinical trials conducted with H5N1 IIV preparations, and this escalated dose was tolerated with minimal adverse events [154]. Similarly, clinical trials with FluBlok have included rHA0 content up to 90 mg for a single HA and 135 mg for trivalent HA preparations [150], with minimal reports of adverse events. Finally, during clinical testing, it was noted that FluBlok preparations demonstrated superior immunogenicity in adult subjects when compared with younger individuals [12]. Recombinant protein vaccines that target non-HA influenza proteins

Although HA is the major target of the immune response, it has been demonstrated experimentally that antibodies toward other influenza virus proteins can lead to protection against virus infection, even if they do not naturally prevent the virus from infecting host cells [155,156]. As vaccine candidates, the non-HA proteins that have been most frequently considered include the NA [157,158] and the M2 ion channel [159]. Specifically, the 22 amino acids of the M2 ion channel, which are expressed on the outer surface of the virus (commonly referred to as the M2 ectodomain or M2e) have been targeted [160]. As discussed above, annual vaccine reformulations have always matched both the HA and the NA component to the selected circulating strain [161,162]. It is worth noting that the NA is immunogenic when delivered alone [163,164], with evidence that antibodies against the NA alone can protect from influenza virus infection [165,166]. Due to the reduced expression of NA at the viral surface [18,167], antibodies toward the NA do not typically prevent infection with the virus, rather they limit the spread of the virus within an infected host [166,168]. Recombinant NA vaccines have been tested in mice [157] and humans [140], and they have demonstrated both safety and immunogenicity. A recent study adequately demonstrated the benefit of anti-NA immunity by showing that vaccination against the NA from H1N1 viruses can protect against H5N1 infection [169]. This finding goes along with the evidence that humans exposed to H1N1 express antiN1 antibodies that recognize the H5N1 NA, which may hint at some level of protection against H5N1 viruses. In addition to the HA and NA proteins, it has been known for decades that an ion channel, M2, exists on the surface of mature influenza A viruses, albeit at low levels [20]. There are 22 amino acids of this ion channel, which are expressed extracellularly, and they are collectively referred to as M2e [159]. This M2e is highly conserved with only a few variants known to occur in nature [170]. Antibodies toward M2e are not strongly induced during infection [171] and the antibodies generated do not neutralize viral particles [172,173]. In fact, antibodies toward M2e are believed to perform their effector function by killing virus-infected cells that express M2e at the cell surface as part of the infection cycle [174]. Specifically, it is believed that natural killer cells [175] and macrophages [176] play a prominent role in the killing of these infected cells, possibly by antibody35

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dependent cellular cytotoxicity, which requires Fc receptor interactions, as demonstrated in mice [176,177]. As another potential application of recombinant protein technology, virus-like particle (VLP) vaccine preparations that utilize HA, NA and M1 proteins have been prepared and tested in both mice and ferrets [178,179]. These VLPs are currently being developed and evaluated in clinical trials by Novavax (Rockville, MD, USA) and Medicago (Durham, NC, USA), and they represent potential vaccines that would induce immunity toward both variable (HA) and moderately conserved (NA) components of influenza viruses [180,181]. The antibodies induced by these VLPs would have the potential to limit infection via interaction with the HA, whereas the antibodies against the NA would be expected to limit virus spread [166], if the host is infected. One interesting VLP approach that has recently been tested in clinical trials involves the use of HA-expressing VLPs produced in plants [182]. Recombinant protein vaccines & correlates of protective immunity

When one considers the correlates of protective immunity against influenza viruses, we currently rely on the HAI assay to quantitate the response of a vaccine toward the HA [183]. This assay has provided an accepted correlate of protection for decades, with an HAI titer of 1:40 established as the gold standard for immunity in the 1970s [184,185]. However, there are times when protection can be seen in the absence of an HAI titer of 1:40, and an HAI titer of 1:40 does not always guarantee protection [186]. Recent efforts to quantitate immunity using the microneutralization assay have demonstrated that this assay is more sensitive at detecting antibodies [187], but a defined titer that represents a correlate of protective immunity using the microneutralization assay has not yet been determined. The topic of correlates of vaccine-induced immunity against influenza viruses has gained increased attention recently, and the discussion has included the definition of correlates that are not based on the interactions between the HA and anti-HA antibodies [188]. If we move toward vaccines that include NA and M2e epitopes, either alone or as components of combination vaccines, we may need to use immune assays that evaluate immunity toward these alternative proteins as we define new correlates of protective immunity that are more appropriate for these vaccine approaches. Expert commentary

For >70 years, influenza vaccines have utilized historical approaches toward design and production that rely on viral intermediates, and it can take 6–9 months to generate a vaccine. Using

these approaches, we have been susceptible to both the minor antigenic drifts in HA gene expression [189], as well as the major antigenic shifts that are associated with pandemics. The recombinant protein technologies that are used to generate vaccines, like the recently approved FluBlok, demonstrate an approach toward vaccine production that can directly induce immunity toward individual components of influenza viruses, without the requirement for a whole virus intermediate. Approval of recombinant protein technology for vaccination against influenza viruses allows for future validation of recombinant protein vaccines designed toward conserved regions of the HA, including recently identified epitopes in the conserved stalk region [190] that can neutralize infection [191–196]. Furthermore, vaccine approaches can be used to target less variable non-HA epitopes, like the NA [197], or the M2 [159] to provide broad, protective immunity. Our first full season of FluBlok vaccine approval, 2013–2014, will provide an excellent test for evaluating vaccine efficacy and effectiveness in a broadly vaccinated population, and will ultimately demonstrate the future application of these vaccine approaches toward preventing illnesses and deaths associated with influenza virus and its complications. Five-year view

The FluBlok vaccine represents the first influenza virus vaccine approved for use by the FDA that can be generated without ever propagating the influenza virus itself. The first 5 years of FluBlok approval will represent an exciting time for recombinant protein vaccine approaches that target the HA, NA and M2e epitopes of influenza viruses. These vaccines can be tested as either individual preparations that target specific epitopes; VLP HA and/or NA preparations; and/or preparations that contain multiple variations of these individual proteins in a manner that optimizes immunity against influenza virus. As presented in this review, many of these vaccines have been created and tested in laboratory and clinical settings, and the success of FluBlok will likely assist in their advancement through clinical approval. Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • Influenza vaccine formulations have evolved since initial use in 1945 to yield the currently available, seasonal influenza vaccines that are safe and immunogenic. • Influenza vaccine production cycles that involve virus intermediates and lengthy reassortment and propagation steps make it difficult to incorporate changes in vaccine formulation in a rapid manner. • Advances in recombinant protein production technologies have led to the recent approval of FluBlok as a recombinant protein vaccine that targets the hemagglutinin surface glycoprotein of influenza viruses.

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adults 50–64 years of age. Vaccine 29(12), 2272–2278 (2011).

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Expert Rev. Vaccines 13(1), (2014)

Influenza vaccines: from whole virus preparations to recombinant protein technology.

Vaccination against influenza represents our most effective form of prevention. Historical approaches toward vaccine creation and production have yiel...
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