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Review

Improving pandemic H5N1 influenza vaccines by combining different vaccine platforms Expert Rev. Vaccines 13(7), 873–883 (2014)

Catherine J Luke and Kanta Subbarao* Emerging Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg 33, Room 3E13C.1, 33 North Drive, MSC 3203, Bethesda, MD 20892-3203, USA *Author for correspondence: Tel.: +1 301 451 3839 [email protected]

A variety of platforms are being explored for the development of vaccines for pandemic influenza. Observations that traditional inactivated subvirion vaccines and live-attenuated vaccines against H5 and some H7 influenza viruses were poorly immunogenic spurred efforts to evaluate new approaches, including whole virus vaccines, higher doses of antigen, addition of adjuvants and combinations of different vaccine modalities in heterologous prime–boost regimens to potentiate immune responses. Results from clinical trials of prime–boost regimens have been very promising. Further studies are needed to determine optimal combinations of platforms, intervals between doses of vaccines and the logistics of deployment in pre-pandemic and early pandemic settings. KEYWORDS: influenza vaccine • pandemic influenza vaccine • prime boost

Influenza viruses & pandemics

Influenza viruses are an ever-present threat to global public health, causing an estimated 250,000–500,000 deaths worldwide annually from seasonal influenza and sporadic pandemics associated with widespread morbidity and mortality [1,2]. Influenza viruses belong to the Orthomyxoviridae family [3]. The genome of influenza A viruses is made up of eight segments of single-stranded, negative sense RNA, encoding at least 10–12 proteins [3,4]. Influenza A viruses are further classified into subtypes, based on the two surface glycoproteins of the virus, hemagglutinin (HA) and neuraminidase (NA). The HA is involved in binding of the virus to host cells and is the major target of neutralizing antibodies. The NA is instrumental in facilitating release and spread of the virus in infected cells and is also an important protective antigen. Antigenic change in the HA protein occurs by two mechanisms, known as antigenic drift and antigenic shift. Antigenic drift is the result of the accumulations of point mutations in the immunodominant head domain of the HA protein. Antigenic drift does not result in a change in

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10.1586/14760584.2014.922416

HA subtype but can sufficiently alter the antigenicity of the HA protein to render vaccines or immunity from prior infection ineffective. Antigenic drift is the main reason for the need to frequently update the component strains of the seasonal influenza vaccine. Influenza A viruses infect a wide range of avian and mammalian species. In nature, the major reservoir of influenza A viruses is aquatic birds, where 16 HA and 9 NA subtypes have been identified. Influenza viruses also infect domestic birds, humans, pigs, horses, dogs, ferrets, mink, whales and seals. Nucleic acids of novel influenza A viruses representing H17N10 and H18N11 subtypes were amplified from bats in South America, suggesting that bats may represent a previously unidentified reservoir of influenza viruses in nature [5,6]. The existence of multiple subtypes is one factor that contributes to the enormous antigenic diversity of influenza A viruses. In addition, the segmented nature of the genome permits exchange, or reassortment, of gene segments between two or more viruses infecting the same cell. Antigenic shift occurs when an influenza A virus undergoes reassortment and acquires a novel HA gene of a different

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subtype. This can result in the emergence of a novel influenza A virus to which the human population has no pre-existing immunity. The virus may acquire other novel gene segments in the reassortment process. If such a virus acquires the ability to transmit efficiently in the human population, this may result in an influenza pandemic. Since the beginning of the 20th century, there have been four influenza pandemics. The 1918–1919 pandemic, or ‘Spanish flu’, was caused by an H1N1 virus and resulted in the deaths of an estimated 40 million people worldwide [7]. The H1N1 virus was replaced by a reassortant H2N2 virus in the 1957 ‘Asian flu’ pandemic when the excess global mortality was estimated at >2 million [1]. In 1968, H3N2 viruses emerged in the ‘Hong Kong pandemic’ that caused an estimated 1 million excess deaths worldwide [1]. In 2009, the first influenza pandemic of the 21st century occurred. This pandemic differed from its three predecessors in that the emergent pandemic virus was of a subtype that was circulating in humans seasonally, H1. However, the HA was derived from swine influenza viruses and was antigenically novel for much of the human population. Interestingly, the HA of the 2009 pandemic H1N1 (2009 H1N1pdm) influenza virus was antigenically related to the 1918 H1N1 virus, and therefore to human H1 influenza viruses that circulated up until 1957, so some level of pre-existing immunity was observed in individuals over the age of 50 [8]. Analysis of H1N1 viruses that circulated in different decades from the 1930s to 1990s revealed that changes in the HA occurred between 1947 and 1950, associated with the presence of a specific glycosylation site, such that prior infection with post-1950 H1N1 viruses could no longer protect against 2009 pH1N1 infection. This provides a mechanistic understanding of the molecular basis for the serological cross-protection observed in people over 60 years of age during the 2009 H1N1 pandemic [9]. The WHO reported 18,631 laboratory-confirmed deaths caused by the 2009 H1N1pdm influenza virus, between April 2009 and August 2010. Recent estimates of global mortality from this pandemic, however, are approximately 10- to 15-fold higher [10,11]. In addition to these widespread outbreaks of influenza viruses of the H1, H2 and H3 subtypes, occasional human infections with other subtypes have occurred. Direct transmission of H5, H7, H9 and H10 influenza A viruses from birds to humans has been reported [12–16]. Since 2003, over 650 cases of H5N1 highly pathogenic avian influenza (HPAI) infection have been confirmed in humans in 16 countries, with 386 deaths [17]. In China, human infections with an H7N9 avian influenza (AI) virus were reported in March 2013. Two waves of human infections with this virus have occurred. As of 21 January 2014, the official number of laboratory confirmed cases reported by the WHO was 207 (133 in the first wave, 73 in the second wave), with a case fatality rate of approximately 20% [18]. However, additional cases have been reported on an almost daily basis through 10 February 2014, and estimates of the unofficial number of cases continue to increase. These 874

human cases of AI infection raise concern of the pandemic potential of these viruses. Influenza vaccines

Two types of vaccines for seasonal influenza are licensed in several countries. Inactivated influenza vaccines (IIV) are the most commonly used, and these are typically split virion vaccines that contain mostly HA protein from inactivated virions [19]. The basis for protection mediated by IIV is primarily a neutralizing antibody response against the immunodominant head region of the HA protein. This correlate of immunity forms the basis for the criteria for licensure of IIV by national regulatory authorities. Live-attenuated influenza vaccines (LAIV) are vaccines based on a weakened influenza virus backbone and contain the HA and NA from the circulating strains of a particular season [20]. LAIV have been shown to consistently elicit anti-HA antibody in young children, but in seropositive older children and adults, antibodies are infrequently detected despite demonstrated efficacy of the vaccine. The correlates of immunity for LAIV have not been determined, but it is thought that mucosal antibody and cell-mediated immunity likely play an important role in protection [21–29]. Many novel platforms for influenza vaccines are being developed and evaluated. In 2013, the first recombinant HA protein vaccine was approved for licensure by the US FDA. It is likely that the next decade will see the advancement of other novel influenza vaccines to licensure. Recently, the discovery of broadly neutralizing monoclonal antibodies derived from individuals who had been infected or vaccinated against influenza, which recognize a highly conserved epitope in the stem region of the influenza HA protein, has driven an international effort to develop universal vaccines for influenza, to provide protection against multiple influenza subtypes [30]. Such vaccines would potentially provide protection against seasonal influenza, without the requirement for frequent updating of the component strains, as well as against potential pandemic influenza viruses that are newly emergent or even those that have yet to emerge. The availability of such broadly protective vaccines is years in the future, but we are learning much from this rapidly evolving field of study of influenza virus biology. Vaccines for pandemic influenza

The unpredictable nature of influenza pandemics and their potential to cause mass illness and mortality demands a high level of preparedness. Vaccines are the most effective means of preventing influenza infection and disease, and over the past decade, huge investments of time and effort have been brought to bear on the development of effective vaccines for pandemic influenza. Most of these efforts have focused on vaccines against H5N1 influenza [31], but vaccines against other subtypes such as H7 and H9N2 have been tested in clinical trials [32–34]. H5N1 viruses have evolved in nature into many clades since their first emergence in humans in Hong Kong in 1997. A list Expert Rev. Vaccines 13(7), (2014)

Prime boost strategies for pandemic influenza vaccines

of pandemic influenza vaccines that have been evaluated in clinical trials since 2007 is available at the WHO website [35]. The following section will summarize the clinical experience with inactivated H5 vaccines as these vaccines have been included in combination vaccine regimens in clinical trials.

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Inactivated H5N1 subvirion vaccines are suboptimally immunogenic

The incursions of HPAI viruses of the H5N1 subtype into the human population beginning in 1997 prompted efforts to develop vaccines against these viruses. With the manufacturing and regulatory infrastructure already in place for the production of seasonal influenza vaccines, this seemed to be the obvious route to take for making vaccines against the newly emerging viruses. However, HPAI H5N1 viruses posed challenges for vaccine production, including the need for high levels of biosafety containment to work with the wild-type viruses, and the fact that the wild-type viruses are lethal for embryonated eggs, the major substrate for inactivated vaccine manufacture [36,37]. Examples of strategies to mitigate these barriers include the use of antigenically related surrogate low pathogenicity H5 viruses as seed viruses for vaccine production [38], the use of reverse genetics to generate nonhighly pathogenic seed viruses [39,40] and the development of cell culture-derived vaccines [41,42]. In response to the reemergence of human infections with H5N1 HPAI viruses beginning in 2003, several manufacturers made inactivated subvirion vaccines (ISVs) based on H5N1 viruses of the A/goose/Guangdong/1996 lineage. The HA of H5N1 viruses from this lineage is evolving, resulting in antigenic drift, which has led to their classification into different clades [43]. Recommended vaccine seed viruses are continually being re-evaluated as the H5N1 viruses evolve [44], but it has not been possible to manufacture and evaluate or to stockpile vaccines representing each clade. For this reason, it is important to identify vaccine approaches that elicit broadly cross-reactive immune responses. The clinical evaluation of inactivated H5N1 vaccines is extensively reviewed elsewhere [31], and only the details of those studies relevant to the combination of vaccine approaches will be discussed here. One of the earliest reports of the clinical evaluation of a vaccine against H5 influenza was the Phase I testing of a vaccine based on the low pathogenicity avian influenza H5N3 virus, A/duck/Singapore/97 [38]. This virus was antigenically related to the HPAI H5N1 viruses that had emerged in Hong Kong in 1997 [45]. The vaccine was administered at various dose levels, in a two-dose regimen, with or without the oil-in-water adjuvant MF59. The vaccine was well tolerated, but was poorly immunogenic without adjuvant, even when twice the amount of HA protein as in the seasonal IIV was given. This was the first indication that H5 influenza subvirion vaccines were not optimally immunogenic in humans. Sixteen months after the initial vaccinations, subjects received booster doses of the same vaccine, again either with or without MF59 adjuvant. Although antibodies were undetectable prior to the boost, a significant boost in antibody titers was observed 21 days later. Importantly, antibody titers were informahealthcare.com

Review

significantly higher in individuals who received the adjuvanted vaccine [46]. In addition, sera from individuals who had been boosted with the adjuvanted vaccine contained antibodies that cross-neutralized antigenically divergent H5N1 viruses that emerged in 2003–2004 [47]. Approximately 7 years after priming with the H5N3 vaccine, subjects returned to receive two doses of 7.5 mg of A/Vietnam/ 1194/2004 (H5N1) ISV [48]. At the time of receipt of this heterologous vaccination, subjects had low levels of A/Vietnam/ 1194-reactive circulating memory B cells. However, 21 days after receipt of the heterologous ISV, a higher frequency of H5N1-specific memory B cells was observed in those individuals who had been primed with the MF59-adjuvanted H5N3 vaccine several years before compared with those subjects who had been primed with the unadjuvanted H5N3 vaccine or had not been primed. The ISV boost elicited high titers of crossreactive H5-specific neutralizing antibody as early as day 7 after vaccination, and titers were significantly higher in primed versus unprimed subjects. These high neutralizing antibody titers were still present 6 months after the boost, suggesting that a pool of cross-reactive memory B cells was generated by the priming vaccination that was rapidly mobilized upon receipt of the antigenically distinct adjuvanted ISV years later. Further analysis of sera from subjects who received the ISV boost by surface plasmon resonance (SPR) provided evidence that antibodies to the HA1 domain of the A/Vietnam/1194/ 2004 virus in the sera of individuals who were primed with the MF59-adjuvanted H5N3 vaccine were of higher affinity than antibodies in subjects who were not primed or were primed with nonadjuvanted vaccine [49]. In 2006, a monovalent A/Vietnam/1203/2004 (H5N1) ISV was evaluated in a Phase I clinical trial [50]. The vaccine was well tolerated, but was only modestly immunogenic, with two doses of 90 mg required to elicit hemagglutination inhibition (HAI) antibody titers of 1:40 or above in 58% of subjects. Six months after the second dose of vaccine, subjects returned for a third booster vaccination [51]. By the time of the third dose, antibody titers had declined in all subjects. A dose-dependent boost in antibody titers was observed after the third dose, with neutralizing antibody titers of 1:40 or greater seen in 78% of subjects who received a third dose of 90 mg, and 67% who received 45 mg. Five months later, neutralizing antibody responses were still significantly higher than those seen after the second dose. Such a vaccination regimen with a delayed third dose may be of use in the event of a pandemic, although high doses of HA were still needed to elicit antibody responses anticipated to be predictive of protection. Belshe and colleagues evaluated accelerated vaccination schedules with inactivated H5N1 vaccines that also included the use of an antigenically distinct inactivated vaccine for the second dose [52]. They found that two doses of 90 mg of the same H5N1 ISV vaccine elicited antibody responses when the second dose was given 7, 14 or 28 days after the first, but HAI and neutralizing antibody titers were lower when the interval was only 7 days, although the difference only achieved 875

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statistical significance for the neutralizing antibody titers. When subjects were primed with a clade 1 H5N1 ISV (A/Vietnam/ 1203/2004) and received a second vaccination with a clade 2 H5N1 ISV (A/Indonesia/05/2005), a boost in antibody titers to the clade 2 virus was observed. Notably, this heterologous boost response was improved when the interval between vaccinations was 6 months compared with 1 month. Such studies provide valuable data for informing vaccination policy for a pandemic response. Production of recombinant subunit vaccines is one approach that obviates the need to work with wild-type viruses for the production of vaccine seeds. Recombinant HA vaccines for seasonal influenza were being developed at the time of the emergence of HPAI H5N1 virus infections in humans, and these vaccines are now licensed (FluBlok; Protein Sciences). A recombinant H5 HA (rH5) vaccine based on the A/Hong Kong/156/1997 (H5N1) isolate was evaluated in a Phase I clinical study reported in 2001 [53]. The protein was produced using the baculovirus expression system. Two doses of the rHA vaccine were administered to H5-naive adult subjects at doses between 25 and 90 mg, at intervals of 21, 28 or 42 days. The vaccine was well tolerated but exhibited only modest immunogenicity, even after two doses of 90 mg, with neutralizing antibody titers of 1:80 or greater being detected in 52% of subjects. There did not appear to be an effect of the length of interval between the doses. Inactivated whole virion H5N1 vaccines have been evaluated in clinical trials and were found to be more immunogenic than subvirion vaccines [41,54–56]. An egg-derived inactivated whole virion H5N1 vaccine based on the influenza A/VN/1194/ 2004 strain elicited an HAI antibody titer of 1:40 or greater in 78% of subjects when given as two doses of 10 mg, 28 days apart, with aluminum hydroxide adjuvant [55]. Antibody titers declined in all dose groups by 28 days after the second dose and had dropped significantly when tested 6 months and 12 months later [56]. A third dose of either 5 or 10 mg of the adjuvanted vaccine administered 12 months after the first dose resulted in a significant boost in antibody titers, with HAI antibody titers of 1:40 or greater in 78.6% of subjects in the 5 mg group, and in 90% of subjects in the 10 mg group [56]. Despite concerns regarding the reactogenicity of inactivated whole virion influenza vaccines, this vaccine was well tolerated, with no serious adverse events reported. The contribution of adjuvant to the observed immunogenicity in these studies could not be determined since comparator groups with nonadjuvanted vaccine were not included. An inactivated whole virion A/VN/1203/2004 H5N1 vaccine produced in Vero cell culture has been evaluated in several clinical trials [41,54,57,58]. This vaccine was administered with or without alum adjuvant and was given in two doses, 21 days apart [41]. The primary immunogenicity end point for this study was neutralizing antibody titer to the vaccine strain, and serum samples were also tested by HAI and single radial hemolysis assay. A neutralizing antibody titer of 1:20 or greater was defined as a response, although this is not established as a 876

correlate of immunity for influenza vaccines. The highest antibody responses were observed in subjects who received two doses of either 7.5 or 15 mg of nonadjuvanted vaccine, with 76.2% and 70.7% of subjects, respectively, with a neutralizing antibody titer of ‡1:20 on day 21 after the second dose. Cross-reactive neutralizing antibody responses against a clade 0 H5N1 virus, A/Hong Kong/156/1997, were detected in 76.2% of subjects in the 7.5 mg group and in 78.0% in the 15 mg group. A lower frequency of cross-reactive neutralizing antibody responses in subjects in these groups was observed against A/Indonesia/5/2005 (H5N1), a clade 2.1.3.2 virus. As with the egg-derived whole virion H5N1 vaccine, this vaccine was well tolerated at all doses tested. Further studies were conducted to assess the persistence of the antibody response at least 12 months after vaccination, and the effect of administration of a booster dose of nonadjuvanted inactivated whole virion H5N1 derived from the A/Indonesia/5/2005 strain [54]. Antibody titers had declined in subjects in all groups, although neutralizing antibody was still detectable 12–17 months after the primary immunizations. A single booster dose of 7.5 mg of the heterologous vaccine resulted in a significant increase in neutralizing antibody titers against homologous and heterologous H5N1 viruses. The safety and immunogenicity of two doses of the nonadjuvanted A/Indonesia/05/2005 inactivated whole virion vaccine was further evaluated in healthy adults and was also found to be well tolerated and elicited neutralizing antibody titers of ‡1:20 in 82.7% (3.75 mg dose) to 86.5% (7.5 mg dose) of subjects. Cross-reactive antibodies against A/Vietnam/1203/ 2004 (H5N1) were detected, and antibodies were found to persist up to 6 months after vaccination. Clinical studies with inactivated whole virion H5N1 vaccines suggest that dose-sparing vaccination regimens are possible with these vaccines, which would be an advantage in a pandemic situation. In summary, the immunogenicity of inactivated subvirion and recombinant HA H5N1 vaccines in humans was not optimal, requiring large doses of antigen or the use of adjuvant to elicit antibody responses. However, the A/VN/1203/2004 H5N1 ISV was approved by the FDA for use in individuals aged 18–64 years who are at increased risk of exposure to the H5N1 influenza virus subtype contained in the vaccine. Although they will not be discussed further in this review, it is important to mention that inactivated vaccines for H7 subtype AI viruses were poorly immunogenic in clinical trials [32,33]. Combining platforms to improve vaccine performance

The idea of using vaccination regimens that combine different vaccine modalities to potentiate the immunogenicity and protective efficacy of vaccines is not new. This approach has been evaluated against several infectious agents, including Plasmodium spp., HIV and Mycobacterium tuberculosis. Multimodality vaccine approaches against these pathogens were designed with the goal of stimulating different arms of the immune response by using different presentations and/or delivery of antigens [59–61]. The regimens are commonly referred to as ‘prime–boost’ regimens, as typically, one modality is used as the ‘priming’ vaccination, and Expert Rev. Vaccines 13(7), (2014)

Prime boost strategies for pandemic influenza vaccines

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Table 1. Clinical trials of prime–boost vaccination regimens for H5N1 pandemic influenza vaccines. Priming vaccine X # doses

Booster vaccine X # doses

Interval

Immunity to homologous virus following boost

Cross-clade Ab response detected?

Ref.

rHA X 2

Heterologous clade ISV X 1

8 years

Increased frequency and magnitude of Ab responses

Yes

DNA X 1 or 2

ISV X 1

4 or 24 weeks

Increased frequency and Ab titers; Ab to HA stem and increased cellular immune responses

Not tested against different H5N1 clades but antibody neutralized low pathogenicity H5N2 virus

DNA X 1

ISV X 1

4, 8, 12, 16 or 24 weeks

Increased frequency and Ab titers; improved quality of Ab; optimal with interval of 12 weeks or longer

Yes

[69,70]

LAIV X 2

ISV, matched or earlier clade, X 1

54–56 months

Increased frequency and magnitude of antibody; rapid, high quality Ab response

Yes

[72,73]

Ad4 vectored vaccine X 3

ISV X 1

3.5–15 months

Increased frequency and magnitude of Ab

Yes

[75]

[53,62]

[68]

Ad4: Adenovirus serotype; LAIV: Live-attenuated influenza vaccine; ISV: Inactivated subvirion vaccine; rHA: Recombinant hemagglutinin.

is followed by a second vaccine type that provides the ‘boost’. ‘Heterologous prime–boost’ is a term that is commonly used to describe such vaccination schedules and specifically refers to a prime–boost regimen where the priming vaccine is different from that used for the boost. Combination strategies for vaccination against pandemic influenza present an attractive option for several reasons. First, vaccine manufacturing capacity is limited, so any strategy that would result in dose sparing is desirable. Second, vaccine regimens that combine multiple modalities offer flexibility in case one type of vaccine is in short supply or is not accessible for some reason. Third, a combination vaccine strategy may potentiate responses to suboptimal immunogens and may elicit broadly cross-reactive responses that could eliminate the requirement for additional vaccinations. Several regimens combining inactivated vaccine with other platforms for pandemic influenza vaccines have been evaluated in animal models and in early-stage clinical trials. They include vaccine modalities that are licensed for use for seasonal influenza vaccines, for example, ISV, recombinant HA and LAIV, as well as investigational vaccines based on platforms that are not yet licensed, including DNA vaccines and adenovirusvectored vaccines. These studies are summarized in the following section and in TABLE 1. Recombinant HA vaccine followed by inactivated vaccine

Eight years after the initial study evaluating the safety and immunogenicity of the rH5 HA [53], a subset of the volunteers who had been vaccinated with the rH5 HA received a single dose of 90 mg of the licensed A/VN/1203/2004 H5N1 ISV. The vaccine was well tolerated and resulted in increased frequency and magnitude of specific HAI and neutralizing antibody responses compared with subjects who received two doses of 90 mg of ISV a month apart [62]. In addition, sera from subjects who had been primed with the rH5 HA vaccine had informahealthcare.com

statistically significantly higher HAI antibody titers against the antigenically distinct H5N1 clade 2.1.3 virus, A/Indonesia/5/ 2005 compared with subjects who had received two doses of ISV. There was no clear relationship between either the priming dose of rH5 HA or the interval between vaccinations and the antibody response to ISV. The authors also reported that there was a suggestion that a detectable response to the initial rH5 HA vaccination was associated with the development of an antibody response to ISV years later. DNA vaccine followed by inactivated vaccine

DNA vaccination is an attractive approach for vaccines against pandemic influenza for several practical reasons. DNA vaccines can be produced rapidly immediately after the genomic sequence of an emergent pandemic strain is available and their manufacture does not require manipulation of live virus. Although DNA vaccines have failed to fulfill their early promise as stand-alone vaccines, it is becoming increasingly clear that DNA vaccines have great potential as part of a combination regimen. In the HIV field, preclinical studies in nonhuman primates of prime–boost regimens using DNA to prime yielded very encouraging data and resulted in the evaluation of such regimens in clinical trials [63–65]. Results from these trials have been mixed and were not always consistent with observations in animal models. However, such studies have provided valuable information for designing future vaccination regimens to elicit effective antibody and cellular immune responses. DNA vaccines have also been explored for pandemic influenza. An H5 influenza plasmid DNA vaccine expressing the HA of influenza A/VN/1203/2004 was evaluated in a Phase I clinical trial in the US [66]. The HA DNA vaccine was administered either as a monovalent vaccine or as part of a trivalent vaccine that also included plasmids encoding the highly conserved influenza A nucleoprotein and M2 ion channel proteins. Two doses of each of the plasmid vaccines were administered 877

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with a proprietary cationic lipid-based adjuvant, 21 days apart. The vaccines were well tolerated, consistent with the favorable safety profile of other experimental DNA vaccines administered to humans. Antibody responses and T cell responses were observed: the monovalent H5 HA vaccine elicited HAI titers of 1:40 or greater and/or fourfold rises in titer in 47–67% of subjects. H5 HA-specific T cell responses were observed in 75–100% of subjects. The results of this study were encouraging and suggested that this platform should be evaluated further, perhaps as part of a vaccination regimen including one or more other vaccine modalities [66]. Preclinical studies in which mice, ferrets and nonhuman primates were primed by immunization with DNA encoding the HA of the 2009 H1N1pdm influenza virus followed by either seasonal IIV or an adenovirus encoding the HA demonstrated that such a regimen could elicit broadly cross-reactive neutralizing antibodies that were directed to the HA stem region [67]. These findings led to a clinical study in which subjects were primed with a DNA vaccine encoding the HA from the A/Indonesia/05/2005 (H5N1) AI virus, followed by vaccination with 90 mg of the A/Indonesia/05/2005 ISV [68]. In this study, one or two priming doses of DNA were administered, and the interval between the last priming vaccination and the receipt of ISV was either 4 or 24 weeks. The DNA prime/ISV boost regimens were well tolerated and elicited higher antibody titers than ISV/ISV regimens, and when the interval between the last dose of DNA and receipt of ISV was 24 weeks, HAI titers anticipated to be predictive of protection were observed in 81% of subjects. No significant difference in antibody responses was observed in individuals who received one versus two priming doses of DNA. Serological analysis was performed on sera obtained between 2 and 4 weeks after the ISV boost, so the kinetics of the antibody response could not be determined. Notably, subjects who received DNA followed by ISV also had antibodies directed at the HA stem. Analysis of a subset of three sera from this group of subjects showed that the antibodies elicited by the DNA/ISV regimen could neutralize an antigenically divergent H5N2 AI virus in an HApseudotyped virus neutralization assay, and two out of three sera neutralized an H9N2 AI virus. Cellular immune responses were also measured by intracellular cytokine staining assay, 4 weeks postreceipt of ISV. DNA priming resulted in a higher frequency of T cell responses, and CD4+ T cell responses were greater than CD8+ responses in these subjects. Further studies examined the interval between the DNA prime and ISV boost [69] in which H5 DNA was followed by ISV at intervals of 4, 8, 12, 16 and 24 weeks. Serology was performed 14 days after receipt of ISV and optimal HAI responses were observed when the interval was 12 weeks or longer: 91% of subjects had HAI responses, with a geometric mean titer (GMT) of 141–206, compared with 55–70% of subjects and a GMT of 51–70 in the shorter interval groups. Neutralizing antibody titers were highest for the groups in which the interval was 16–24 weeks, and ELISA titers were highest when the interval was 24 weeks. Antibody to the HA stem was detected in all 878

groups, and a trend towards broader cross-reactivity of neutralizing antibody was observed in the groups with an interval of 12 weeks or longer. The interval between doses did not have any effect in subjects who received two doses of ISV in this study. Qualitative analysis of the sera from these DNA/ISV vaccination studies using a genome-fragment phage display library and SPR revealed that DNA priming expanded the H5-specific antibody repertoire and enhanced antibody avidity to the HA1 portion of H5 HA compared with antibody produced in response to ISV/ISV vaccination [70]. In addition, the interval between DNA and ISV was important for the quality of the antibody response; regimens with an interval of 12 weeks or longer elicited higher avidity antibody that was more broadly cross-reactive with H5N1 viruses from different clades. Live-attenuated vaccine followed by inactivated vaccine

Live-attenuated vaccine is an appealing platform for development of vaccines for pandemic influenza for several reasons. Compared with IIV, LAIV are relatively easy to manufacture, generally have a higher yield in eggs and employ needle-free delivery. From a biological standpoint, LAIV replicate in the upper respiratory tract, and so they mimic natural influenza infection and generate mucosal and cellular immune responses including secretory IgA [20]. LAIV is licensed for use in several countries. In the US, the licensed LAIV is marketed as FluMist, which is based on cold-adapted influenza A and B master-donor viruses [71]. An LAIV that was developed in Russia, based on a different cold-adapted donor virus strain, is licensed in some countries. Several LAIVs based on influenza viruses of pandemic potential have been evaluated in Phase I clinical trials. Two H5N1 LAIVs, manufactured using the FluMist backbone and administered in two doses of 107.5 50% tissue culture infectious doses, were found to be well tolerated but highly restricted in replication in healthy adults [72]. HAI and neutralizing antibody responses were observed in only 10 and 5%, respectively, of subjects who received an A/Vietnam/1203/2004 (H5N1)-based LAIV (VN04 LAIV), although a higher frequency of responses was observed by IgG and IgA ELISA (38 and 52%, respectively). Responses to an H5N1 LAIV with the HA and NA from an antigenically distinct H5N1 virus, A/HK/213/ 2003 – HK03 LAIV, were even lower. Because the subjects in these studies were seronegative to H5 viruses, a higher frequency and magnitude of HAI and neutralizing antibody responses were expected and the significance of ELISA antibody responses is not known because reliable immune correlates of protection for LAIV have not been identified. The promising data from combination vaccination regimens for H5N1 vaccines led us to design a clinical study in which individuals who had previously received two doses of the H5N1 VN04 or H5N1 HK03 LAIV vaccines were invited to return to the clinical study site to receive a single dose of 45 mg of the A/VN/1203/2004 (H5N1) ISV [73]. We also hypothesized that if immunological memory had been established by the H5N1 LAIV vaccinations, we would see an increased frequency and higher antibody response in H5N1 LAIV-primed individuals than in unprimed individuals. Expert Rev. Vaccines 13(7), (2014)

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Prime boost strategies for pandemic influenza vaccines

Subjects who received two doses of the antigenically matched H5N1 VN04 LAIV almost 5 years previously [72] had an increased frequency (82 vs 50%) and significantly greater magnitude of HAI responses (112 vs 76 GMT) compared with H5N1-naive subjects who had received two doses of 45 mg of ISV 1 month apart. Interestingly, antibody responses in previous recipients of H5N1 LAIV were rapid: 64% of subjects who previously received H5N1 VN04 LAIV had fourfold rises in HAI antibody titer by day 7 following receipt of ISV, with a GMT of 165 (range 20–1280 in responders). The kinetics of the antibody response are consistent with B cell memory responses [48]. Antibody responses with similar kinetics but of lower frequency and titer were observed in individuals who initially received the antigenically distinct H5N1 HK03 LAIV. Sera from subjects previously immunized with H5N1 LAIV were able to neutralize H5N1 AI viruses from other clades in the A/goose/Guangdong/96 lineage. SPR analysis of sera demonstrated higher avidity antibody to a recombinant HA1 of the H5 HA in subjects who had previously received H5N1 LAIV similar to the findings in the DNA/ISV H5 study [70]. Antibody avidity correlated with neutralization of antigenically distinct H5N1 viruses. These findings clearly demonstrate that the H5N1 LAIVs had effectively primed for a long-lived memory response that resulted in production of high-titer, high-quality antibodies following receipt of ISV. The kinetics of the antibody response suggest that the ISV vaccine is unmasking the response established by the initial LAIV vaccination. Based on these observations, it is tempting to speculate that a natural exposure to a replicating H5N1 AI virus could potentially recall protective levels of antibody in LAIV-primed individuals. Antibodies directed at HA stem were not assessed in this study, but HAI and neutralizing antibody titers correlated well and qualitative analysis of the serological response suggests that most of the antibody was directed towards the immunodominant region of the HA located in HA1. The mechanism of priming by LAIV remains to be determined. Bentebibel et al. reported that a subset of T helper cells of the ICOS+CXCR3+CXCR5+ phenotype were found to play a pivotal role in the induction of antibodies following receipt of IIV, but only in those individuals who had been previously primed [74]. These cells may be present in individuals primed not only with LAIV, but also by other vaccine modalities. Since LAIV are replicating virus vaccines with a theoretical risk of reassortment with circulating human influenza viruses, they cannot be used in a pre-pandemic setting. However, they could be used early in an emergent pandemic situation. Therefore, it is important to determine how the interval between LAIV and ISV influences the antibody response. Vectored vaccine expressing H5 HA followed by inactivated vaccine

Adenoviral vectors are being evaluated for development of vaccines against several pathogens, especially HIV. Benefits of using replication-deficient adenovirus-based vaccines include safety and their ability to generate potent cellular and antibody responses. Adenovirus-based vaccines could be used in a pre-pandemic informahealthcare.com

Review

setting, making them an attractive option for pandemic vaccine development. Careful selection of the particular adenovirus to be used is important since pre-existing immunity in the human population to certain types of adenovirus may result in reduced vaccine effectiveness. Gurwith et al. reported a Phase I clinical trial of the safety and immunogenicity of an adenovirus serotype 4 (Ad4) vector vaccine for H5N1 influenza [75]. Healthy adults received three immunizations with one of five doses of the Ad4 vaccine expressing the HA from the clade 1 H5N1 virus, A/VN/1194/2004. Doses ranged from 107 virus particles to 1011, in 10-fold increments and vaccine was given at intervals of about 56 days followed 3.5–15.5 months later with a single dose of 90 mg of the A/VN/1203/2004 ISV. HAI responses to the initial Ad4 vaccination series were low, with seroconversion observed in only 11% of vaccinees, with a GMT of 6. A single dose of ISV resulted in higher frequency and magnitude of the antibody response. After ISV, 100% of subjects who had received 1011 Ad4 virus particles seroconverted, with a GMT of 135, compared with 36% seroconversion and a GMT of 13 in subjects who had initially received placebo. Eighty-nine percent of the 1011 Ad4 cohort had HAI titers considered to be protective compared with 18% of placebo recipients. Ninety-four percent of vaccinees who had an HAI titer of 1:80 or greater to clade 1 A/Vietnam H5N1 virus had HAI titers of 1:40 or greater against the clade 2.1 virus, A/duck/Hunan/2002 (H5N1), suggesting that the Ad4/ISV regimen elicited cross-clade antibody responses. T cell responses were measured by IL-2 and IFN-g ELIspot. A higher frequency of IFN-g ELIspot responses was observed in Ad4 vaccine recipients compared with placebo recipients, with responses observed in 70% of vaccinees in the 1011 Ad4 cohort. Similar results were seen with the IL-2 ELIspot. The authors reported that preliminary data suggest that the responses are predominantly CD4+-cell mediated. The adenovirus vaccine was well tolerated, with no serious adverse events occurring even at high doses. This study demonstrated that the immunogenicity of H5N1 ISV could be enhanced by priming with an adenovirus-vectored vaccine. Further studies are needed to determine the effect of changing the interval between Ad4 and ISV, the number of priming doses of Ad4 and the feasibility of using lower doses of ISV for antigen sparing. In summary, the development of pandemic influenza vaccines has been challenging not only because of relatively poor immunogenicity of H5 viruses but also because of manufacturing obstacles. In the event of a pandemic, the current global vaccine manufacturing capacity would be woefully inadequate for the production of sufficient vaccine, even at the doses that are currently used for seasonal vaccine. The need for the high doses of antigen for H5 inactivated vaccines to elicit antibody responses has forced those working in this field to explore new vaccine modalities, such as recombinant HA and DNA vaccines. Many of these new vaccine approaches are not yet licensed. However, vaccination regimens that combine different platforms and technologies with inactivated vaccine are being explored. Such regimens may have both practical and biological benefits, allowing 879

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for dose sparing and increased breadth of immunity against antigenically divergent influenza viruses.

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Other emerging vaccine platforms for pandemic influenza

Several new vaccine technologies are being evaluated for both seasonal and pandemic influenza. Promising platforms include virus-like particles [76–78], poxvirus and adenovirus-vectored vaccines [79–82] and other replication-deficient LAIV platforms, such as NS-1 deletion or knockout mutants [83–86], M2 deletion mutants [87,88] and HA signal-deficient pseudotyped influenza A viruses [89]. These vaccine modalities are currently being evaluated in preclinical and/or clinical studies and may eventually be incorporated into multiplatform vaccine regimens.

implemented. Further research is needed to define the correlates of protection for non-HA based and novel vaccine candidates so that clinical studies to support licensure of new vaccines can be efficiently and robustly designed. In addition, pathways to licensure must be developed for vaccine regimens combining different platforms. We have highlighted combination regimens that include both licensed and unlicensed vaccine platforms. Regulatory requirements for approval of such approaches must be developed. A unique regulatory hurdle for pandemic influenza vaccines is that efficacy trials of these vaccines cannot be conducted in humans. Research designed to determine the mechanism of priming in multiplatform vaccine regimens will also be of interest. Financial & competing interests disclosure

Expert commentary & five-year view

The field of influenza vaccine development that includes pandemic, seasonal and universal vaccines is moving rapidly. In the next 5 years, it is critical that different vaccination regimens be evaluated in a systematic manner in animal models and in clinical trials. Vaccine regimens designed to elicit broadly crossreactive antibodies, including those directed at the HA-stem and regimens that allow dose sparing should be a priority. More established technologies such as nonadjuvanted whole virus vaccines could also be investigated. In response to the evaluation and anticipated success of these regimens in clinical trials, a regulatory framework for approval of novel vaccine technologies for influenza must be

This research was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. CJ Luke is a member of the Executive Committee for a Cooperative Research and Development Agreement between NIH and MedImmune. K Subbarao is Principal Investigator on a Cooperative Research and Development Agreement between NIH and MedImmune for the development of liveattenuated pandemic influenza vaccines. The authors have no other 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 apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues • In recent years, there has been an explosion in the field of vaccine development for influenza, including efforts to develop practical and effective pandemic influenza vaccines, and universal influenza vaccines. • Inactivated vaccines against potential pandemic strains of avian influenza are uniformly suboptimal in immunogenicity in humans. • Several vaccination regimens that include a heterologous priming modality followed by inactivated vaccine boost show promise in early clinical trials in humans. • Different combinations of prime and boost vaccine platforms should be compared for their ability to enhance immunogenicity of pandemic influenza vaccines. • Clinical and nonclinical studies should be conducted to determine the optimal interval between different vaccine modalities and the importance of the order in which the vaccines are administered. Such studies will be of great value in informing pandemic vaccine policy.

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Improving pandemic H5N1 influenza vaccines by combining different vaccine platforms.

A variety of platforms are being explored for the development of vaccines for pandemic influenza. Observations that traditional inactivated subvirion ...
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