Avian influenza vaccines

INTRODUCTION — Avian influenza viruses are important viruses of pandemic potential. Outbreaks of avian influenza viruses among poultry and wild bird populations have prompted increased interest in pandemic preparedness.

Issues related to avian influenza vaccines for human use will be reviewed here.

Issues related to the epidemiology, transmission, pathogenesis, clinical manifestations, diagnosis, and treatment of avian influenza are discussed separately. (See "Avian influenza: Epidemiology and transmission" and "Avian influenza: Clinical manifestations and diagnosis" and "Avian influenza: Treatment and prevention".)

AUTHORIZED VACCINES — Pandemic-specific vaccines must be distinguished from prepandemic vaccines:

●Pandemic-specific vaccines are developed only once a pandemic has been declared and the culprit virus has been characterized.

●To reduce delay, prepandemic vaccines are developed and authorized for use (but not marketed) prior to declaration of a pandemic [1]. In the event of a pandemic, the manufacturer can include the emerging virus subtype in the previously authorized vaccine then apply for final authorization. Ideally, this would facilitate expedition of the approval process since the safety and efficacy of the vaccine have already been assessed.

There are several prepandemic vaccines authorized for human use in the United States and European Union that could be modified into pandemic-specific vaccines if a pandemic is declared. These are summarized in the table (table 1).

HUMAN VACCINE DEVELOPMENT

Challenges and novel approaches — There have been multiple challenges to the development of avian influenza vaccines; these include:

●Genetic evolution (with several antigenically diverse virus clades and subclades) poses difficulty in selecting the best viruses from which to prepare vaccines. This challenge could be mitigated by the development of a universal influenza virus vaccine. Use of prime-boosting is another area of study; it consists of immunizing (or priming) an immunologically naïve individual, followed by subsequent boosting (potentially many years later) with a heterologous vaccine, to induce rapid cross-clade seroprotection [2] .

●Avian influenza antigens are poor inducers of immunogenicity in humans [3,4]. Several vaccine doses may be required to induce seroprotection (which is logistically challenging in an emergency situation). The use of adjuvants or live attenuated viruses is beneficial to induce a more robust immune response with a lower quantity of antigen; this is important for expediting the induction of immunity as well as optimizing vaccine supply.

●Serologic tests for the detection of antibody to avian influenza are not standardized, and results are variable among laboratories; it is difficult to compare results between vaccine studies [5]. Setting an international standard for antibody detection is important for standardization of vaccine immunogenicity and for determining correlates of immune protection needed for vaccine approval [6].

●Highly pathogenic avian influenza (HPAI) viruses may be lethal to chickens, whose eggs are usually used for large-scale vaccine production. Careful attention to biosecurity in chicken facilities is important to minimize the risk of avian influenza virus contamination. Development of alternative vaccine production techniques (described below) has been important to reduce reliance on egg-based vaccine production.

Current approaches for influenza vaccine development include [7]:

●Inactivated egg-grown vaccine (including whole-virion and subvirion vaccine).

●Adjuvanted vaccines, including subvirion, inactivated whole-virion, and virosome vaccines; adjuvants include oil-in-water emulsions such as MF59 and AS03, aluminum hydroxide, and aluminum phosphate.

●Cell culture-derived inactivated whole-virus vaccine.

●Live attenuated intranasal virus vaccine.

●mRNA vaccines − The rapid rollout of mRNA vaccine technology against SARS-CoV-2 infection has pushed mRNA vaccine platform technology to the forefront of clinical development. mRNA vaccines deliver transcripts encoding viral proteins to cells that synthesize and express these proteins, inducing antibody and cellular responses [8-10].

●Adenovirus-based influenza vaccines – Adenovirus-based vaccines, which were developed and used to prevent SARS-CoV-2 infections, are also being investigated for the prevention of influenza [11].

●Plant-based recombinant influenza vaccines [12].

Avian influenza H5N1

Nonadjuvanted vaccine — The United States National Stockpile includes a nonadjuvanted subvirion H5N1 avian influenza vaccine (Sanofi 2007) (table 1). The vaccine is intended for use in adults 18 to 65 years of age and is given as two doses one month apart.

The safety and efficacy were evaluated in a randomized trial including 451 healthy adults [13]. Participants received two doses of vaccine (containing 90, 45, 15, or 7.5 mcg of hemagglutinin [HA] antigen or placebo). Immunogenicity was poor; the only group in which more than half of subjects reached the predefined immunogenicity threshold was the group that received 90 mcg (a total dose nearly 12 times that of seasonal influenza vaccines) [14]. The vaccine was well tolerated; the most common side effects were pain at the injection site, headache, malaise, and muscle pain.

In a follow-up study, 337 participants received a third vaccine dose (containing 90, 45, 15, or 7.5 mcg of HA antigen). One month later, microneutralization geometric mean titers were ≥1:40 in 78, 67, 43, and 31 percent of recipients in each group, respectively [15]. Five months later, microneutralization geometric mean titers remained significantly greater than titers after the second dose; these findings suggest that after priming with vaccine, antibody responses can be further enhanced by vaccine boosting.

Adjuvanted vaccines — Adjuvants facilitate administration of lower doses of antigen; in addition, they have potential to increase vaccine production capacity [16,17]. Oil-in-emulsion adjuvanted vaccines (AS03 and MF59), but not alum-adjuvanted vaccines, are associated with better overall immune responses [18-23] and have been authorized for use as prepandemic vaccines.

Some of these "antigen-sparing" approaches have used subvirion or whole-virion vaccine design.

Subvirion vaccines

AS03 — An AS03-adjuvanted recombinant H5N1 split-virion vaccine has been authorized as a prepandemic vaccine for use in the United States (2013) and Europe (2009) (table 1). These vaccines are immunogenic against the homologous vaccine strain and also induce cross-clade neutralizing antibodies against antigenically distinct H5N1 viruses [20,24-26].

The safety and efficacy of this vaccine formulation were evaluated in a randomized trial including 400 healthy adults 18 to 60 years of age [20]. Participants received two doses of vaccine 21 days apart; four antigen doses (3.8, 7.5, 15, and 30 mcg HA, with or without AS03) were administered. Among participants who received adjuvanted vaccine, all doses ≥7.5 mcg induced adequate seroprotection after the first vaccine dose; all doses (including the lowest dose of 3.8 mcg) induced adequate seroprotection after the second vaccine dose. The nonadjuvanted vaccines were poorly immunogenic.

In another study, a two-dose regimen of an even lower dose (1.9 mcg) of AS03 adjuvanted H5N1 vaccine was more immunogenic (92 percent had a fourfold increase in microneutralization titers versus 42 percent) and induced a higher proportion of cross-neutralizing antibodies (39 to 65 percent versus 7 percent) compared with 7.5 mcg of nonadjuvanted vaccine [24]. In subsequent studies enrolling individuals >61 years of age, a two-dose series of 3.75 and 7.5 mcg of AS03-adjuvanted vaccine given 21 days apart induced adequate seroprotection [25,26].

In a subsequent trial including more than 300 adults age 18 to 64 years, participants were randomly assigned to receive an AS03 subvirion vaccine containing 3.75 mcg of the HA antigen 21 days apart, 14 days apart, 7 days apart, or on the same day [27]. Each of the accelerated schedules met predetermined immunogenicity licensing criteria.

The most common adverse effect of AS03-adjuvanted vaccine is injection site pain; other adverse effects include myalgia, headache, fatigue, and injection site redness and swelling.

MF59 — An MF59-adjuvanted H5N1 vaccine has been authorized as a prepandemic vaccine for use in the United States (Audenz 2020) and Europe (Aflunov 2010, Foclivia 2011) (table 1).

The efficacy of this formulation was evaluated in a trial including 394 healthy adults who were randomly assigned to receive placebo, vaccine alone (45, 30, or 15 mcg per dose), vaccine adjuvanted with MF59 (15 or 7.5 mcg per dose), or vaccine adjuvanted with aluminum hydroxide (30, 15, or 7.5 mcg) [21]. One month after the second vaccine dose, seroprotection was observed more frequently among those who received the MF59-adjuvanted (15 mcg dose) vaccine than the nonadjuvanted (45 mcg dose) vaccine (63 versus 29 percent).

Other trial data evaluating MF59-adjuvanted H5N1 vaccine suggest that prepandemic priming could be incorporated into seasonal influenza immunization schedules [28-30].

Whole-virion vaccines — A Vero cell-derived whole-virion vaccine was authorized as a prepandemic vaccine for use in Europe (Baxter 2009) (table 1).

The immunogenicity of this formulation was evaluated in phase I and II randomized trials among 275 volunteers who received two doses of vaccine 21 days apart (containing 3.75 mcg, 7.5 mcg, 15 mcg, or 30 mcg of HA antigen with alum-adjuvant or 7.5 or 15 mcg of HA antigen without adjuvant) [31]. The vaccine induced neutralizing antibodies against the clade 1 virus strain used in the vaccine as well as cross-reactive antibodies against clade 2 and 3 strains; the most favorable responses were observed with 7.5 or 15 mcg of HA antigen without adjuvant.

In a follow-up study, a subset of the individuals received a booster containing 7.5 mcg of HA antigen without adjuvant from an antigenically distinct clade 2.1 strain, 12 to 17 months after the priming regimen [32]. The prime-boost regimen resulted in higher cross-reacting antibody responses against clades 1, 2.1, 2.2, and 2.3 viruses than those induced after the priming regimen.

Alternative whole virus vaccine candidates have proved immunogenic in several studies [31-36].

Live attenuated intranasal vaccine — Live attenuated influenza vaccines containing HA and neuraminidase genes from seasonal influenza viruses are already licensed in the United States. In a pandemic situation, this vaccine formulation would be advantageous due to its high growth yield in eggs and the induction of mucosal immunity that is cross-reactive to antigenically distinct strains.

Two candidate live attenuated H5N1 vaccines were found to be restricted in replication and only modestly immunogenic after two doses among 59 healthy adults [37]. In a follow-up study five years later, a single dose of nonadjuvanted subunit influenza H5N1 vaccine was administered to individuals primed by live attenuated H5N1 vaccine as well as naïve individuals; greater antibody response was observed among the primed individuals, indicating live attenuated vaccine had induced long-lasting B cell memory [38].

Avian influenza H7N9 — There is no influenza A/H7N9 vaccine currently available for human use. A number of A/H7N9 vaccine candidates have been evaluated; these include:

●A/Anhui/1/2013 H7N9 vaccine [39,40]

●A/Shanghai/2/2013 H7N9 vaccine [40-42]

PANDEMIC PREPAREDNESS — Factors likely to delay widespread availability of pandemic-specific vaccine include production capacity, distribution logistics, and two-dose administration schedules. Additional challenges include limitations in adjuvant availability as well as secondary manufacturing issues such as syringe filling and vaccine formulation.

●Stockpiling – Advance vaccine production and stockpiling of antigen and adjuvants may be beneficial to reduce limitations associated with vaccine availability. Some governments (including that of the United States) have stockpiled H5N1 vaccine and liquid adjuvant formulations as part of preparedness planning. However, antigenic diversity of circulating H5N1 viruses may mean that any vaccine prepared in advance may not be well matched to the eventual outbreak strain.

●Shelf life of stored antigen – The shelf life of stored bulk antigen is uncertain; one study of AS03A-adjuvanted H5N1 vaccine formulated with bulk antigen that had been stored for four years found that immune responses were similar to those elicited by newly manufactured vaccine [43].

In one randomized trial, influenza H5N1 antigen was administered with and without MF59 adjuvant using material from the United States National Pre-Pandemic Influenza Vaccine Stockpile [44]. At the time of immunization, the oldest stockpiled influenza H5N1 antigen was 12 years old, and the oldest stockpiled MF59 adjuvant was 7 years old. The tolerability and immunogenicity were comparable with historic clinical trial data, despite the extended storage years of antigen or adjuvant.

SUMMARY

●Authorized vaccines – Pandemic-specific vaccines are developed once a pandemic has been declared and the culprit virus has been characterized. To reduce delay, prepandemic vaccines are developed and authorized for use (but not marketed) prior to declaration of a pandemic. Prepandemic vaccines authorized for human use are summarized in the table (table 1). (See 'Authorized vaccines' above.)

●Challenges to vaccine development – There are a number of challenges to development of avian influenza vaccines. Genetic evolution (with several antigenically diverse virus clades and subclades) poses difficulty in selecting the best viruses from which to prepare vaccines. In addition, avian influenza antigens are poor inducers of immunogenicity in humans, and serologic tests for detection of antibody to avian influenza are not standardized. (See 'Challenges and novel approaches' above.)

●Novel approaches – Highly pathogenic avian influenza (HPAI) viruses may be lethal to chickens, whose eggs are used for large-scale vaccine production. Novel approaches include adjuvanted vaccines, cell culture-derived vaccines, live attenuated intranasal vaccines, and mRNA vaccines. (See 'Challenges and novel approaches' above.)

●Stockpiling – Advance vaccine production and stockpiling of antigen and adjuvants may be beneficial to reduce limitations associated with vaccine availability. (See 'Pandemic preparedness' above.)