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خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : -22 مورد

Avian influenza vaccines

Avian influenza vaccines
Author:
Iain Stephenson, MD, FRCP
Section Editors:
Martin S Hirsch, MD
Michael G Ison, MD, MS
Deputy Editor:
Elinor L Baron, MD, DTMH
Literature review current through: Apr 2025. | This topic last updated: Apr 25, 2025.

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.

●Messenger RNA (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

Adult formulations

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 participants 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

●ASO3 – 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 aged 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, seven 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 [24-27].

●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].

Pediatric formulations — Alum adjuvant, oil-in-emulsion adjuvant (ASO3 and MF59), and whole-virion vaccines have been assessed in several studies in children 6 months to 17 years of age; they have been generally well tolerated.

●An aluminum-phosphate adjuvant H5N1 split-virion vaccine (two doses containing 30 mcg or 45 mcg HA, separated by 21 days) was evaluated in 150 children >6 months to nine years of age [39]. The vaccine was well tolerated and strongly immunogenic, with >95 percent of recipients achieving fourfold increases in neutralizing or hemagglutination inhibition (HAI) antibody responses.

●A Vero cell-derived whole-virion H5N1 vaccine (two doses containing 3.75 mcg or 7.5 mcg HA, separated by 21 days) was evaluated in a randomized trial involving 72 children aged 6 to 35 months and 303 children aged three to eight years [40].

●Both doses were well tolerated. Mild local reactions were reported in 16 to 19 percent of those aged 6 to 35 months and 24 to 26 percent of those aged three to eight years. Fever was reported among 16 to 19 percent of those aged 6 to 35 months and 4 to 6 percent of three to eight years.

●Fourfold increases in neutralizing antibodies were observed following the 3.75 mcg dose among those aged 6 to 35 months and three to eight years (60 and 53.4 percent, respectively), and following the 7.5 mcg dose among those aged 6 to 35 months and three to eight years (65.6 and 72.2 percent, respectively).

●An MF59-adjuvant H5N1 vaccine (two doses of 3.75 mcg or 7.5 mcg HA) was evaluated among 662 children aged 6 months to 17 years of age [41]. The vaccine was well tolerated with mild local reactions reported among recipients <6 years of age (47 to 50 percent) and >6 years of age (67 to 68 percent). Vaccine doses were strongly immunogenic, with overall seroconversion rates of 86 percent following the 3.75 mcg dose and 96 percent following the 7.5 mcg dose. The highest seroconversion rates were observed among children aged 6 to 35 months, with 94 to 97 percent responses to 3.75 mcg and 7.5 mcg.

●An ASO3B-adjuvanted H5N1 vaccine (two doses of 1.9 mcg) was evaluated among 607 children aged 6 months to 17 years [42]. Among age groups 6 to 35 months, 3 to 8 years, and 9 to 17 years, neutralizing antibody responses were observed in 100, 100, and 97.5 percent of recipients, respectively. Seroprotective HAI titers >1:40 were observed in 100, 99.5, and 99.5 percent of recipients. Fever was observed among age groups 6 to 35 months, 3 to 5 years, 6 to 8 years, and 9 to 17 years in 22, 15, 13, and 2 percent, respectively. Pain at the injection site occurred in 67 percent of children in the vaccine group.

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

●A/Anhui/1/2013 H7N9 vaccine [43,44]

●A/Shanghai/2/2013 H7N9 vaccine [44-46]

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.

●Virus selection – Candidate vaccine viruses are identified through global and regional efforts. Global outbreak surveillance identifies current circulating avian influenza viruses and newly emerging antigenically distinct strains that can be used to update the antigen for approved H5 vaccines.

●Stockpiling – Advance vaccine production and stockpiling of antigen and adjuvants may be beneficial to reduce limitations associated with vaccine availability. Some governments (including the United States) have stockpiled H5N1 and H5N8 vaccine and liquid adjuvant formulations as part of preparedness planning [47]. 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.

●Prepandemic vaccination – Following widespread H5N1 activity among wild and domestic birds in Europe and the United States, with several spillover events to mammals (including mink farms and dairy cattle herds), Finland was the first country to recommend vaccination with a prepandemic vaccine for at-risk individuals. The zoonotic influenza vaccine, based on the H5N8 strain, is expected to provide immune protection against clade 2.3.4.4b avian H5N1 influenza; it has been recommended in Finland for adults >18 years of age in occupational risk groups, including fur farm workers, poultry workers, veterinarians, and laboratory personnel [48].

●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 [49].

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 [50]. At the time of immunization, the oldest stockpiled influenza H5N1 antigen was 12 years old, and the oldest stockpiled MF59 adjuvant was seven years old. The tolerability and immunogenicity were comparable with historic clinical trial data, despite the extended storage years of antigen or adjuvant.

SUMMARY AND RECOMMENDATIONS

●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 messenger RNA (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.)

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Topic 7000 Version 39.0

References

1 : Vaccines for pandemic influenza. Human regulatory, European Medicines Agency. https://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/pandemic-influenza/vaccines-pandemic-influenza (Accessed on March 21, 2023).

2 : Antigenically distinct MF59-adjuvanted vaccine to boost immunity to H5N1.

3 : Boosting immunity to influenza H5N1 with MF59-adjuvanted H5N3 A/Duck/Singapore/97 vaccine in a primed human population.

4 : Safety and antigenicity of whole virus and subunit influenza A/Hong Kong/1073/99 (H9N2) vaccine in healthy adults: phase I randomised trial.

5 : Comparison of neutralising antibody assays for detection of antibody to influenza A/H3N2 viruses: an international collaborative study.

6 : Reproducibility of serologic assays for influenza virus A (H5N1).

7 : Development of vaccines against influenza H5.

8 : Preclinical and Clinical Demonstration of Immunogenicity by mRNA Vaccines against H10N8 and H7N9 Influenza Viruses.

9 : mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials.

10 : Promising strategy for developing mRNA-based universal influenza virus vaccine for human population, poultry, and pigs- focus on the bigger picture.

11 : Adenoviral Vectors as Vaccines for Emerging Avian Influenza Viruses.

12 : Plant-based rapid production of recombinant subunit hemagglutinin vaccines targeting H1N1 and H5N1 influenza.

13 : Safety and immunogenicity of an inactivated subvirion influenza A (H5N1) vaccine.

14 : Vaccines against avian influenza--a race against time.

15 : Evaluation of the safety and immunogenicity of a booster (third) dose of inactivated subvirion H5N1 influenza vaccine in humans.

16 : Cross-reactivity to highly pathogenic avian influenza H5N1 viruses after vaccination with nonadjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a potential priming strategy.

17 : Pandemic preparedness: lessons learnt from H2N2 and H9N2 candidate vaccines.

18 : Safety and antigenicity of non-adjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a randomised trial of two potential vaccines against H5N1 influenza.

19 : Safety and immunogenicity of an inactivated split-virion influenza A/Vietnam/1194/2004 (H5N1) vaccine: phase I randomised trial.

20 : Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial.

21 : Effects of adjuvants on the safety and immunogenicity of an avian influenza H5N1 vaccine in adults.

22 : Safety and immunogenicity of an inactivated influenza A/H5N1 vaccine given with or without aluminum hydroxide to healthy adults: results of a phase I-II randomized clinical trial.

23 : Safety and cross-reactive immunogenicity of candidate AS03-adjuvanted prepandemic H5N1 influenza vaccines: a randomized controlled phase 1/2 trial in adults.

24 : An adjuvanted, low-dose, pandemic influenza A (H5N1) vaccine candidate is safe, immunogenic, and induces cross-reactive immune responses in healthy adults.

25 : Immunogenicity profile of a 3.75-μg hemagglutinin pandemic rH5N1 split virion AS03A-adjuvanted vaccine in elderly persons: a randomized trial.

26 : Dose-sparing H5N1 A/Indonesia/05/2005 pre-pandemic influenza vaccine in adults and elderly adults: a phase III, placebo-controlled, randomized study.

27 : Rapid immunization against H5N1: a randomized trial evaluating homologous and cross-reactive immune responses to AS03(A)-adjuvanted vaccination in adults.

28 : Immunogenicity of avian influenza A/Anhui/01/2005(H5N1) vaccine with MF59 adjuvant: a randomized clinical trial.

29 : Combined, concurrent, and sequential administration of seasonal influenza and MF59-adjuvanted A/H5N1 vaccines: a phase II randomized, controlled trial of immunogenicity and safety in healthy adults.

30 : A phase II study of an investigational tetravalent influenza vaccine formulation combining MF59®: adjuvanted, pre-pandemic, A/H5N1 vaccine and trivalent seasonal influenza vaccine in healthy adults.

31 : A clinical trial of a whole-virus H5N1 vaccine derived from cell culture.

32 : A cell culture (Vero)-derived H5N1 whole-virus vaccine induces cross-reactive memory responses.

33 : Safety and immunogenicity of a modified-vaccinia-virus-Ankara-based influenza A H5N1 vaccine: a randomised, double-blind phase 1/2a clinical trial.

34 : Induction of Cross-Clade Antibody and T-Cell Responses by a Modified Vaccinia Virus Ankara-Based Influenza A(H5N1) Vaccine in a Randomized Phase 1/2a Clinical Trial.

35 : The safety and immunogenicity of a cell-derived adjuvanted H5N1 vaccine - A phase I randomized clinical trial.

36 : Immunogenicity, safety, and cross-reactivity of an inactivated, adjuvanted, prototype pandemic influenza (H5N1) vaccine: a phase II, double-blind, randomized trial.

37 : Evaluation of two live attenuated cold-adapted H5N1 influenza virus vaccines in healthy adults.

38 : A live attenuated influenza A(H5N1) vaccine induces long-term immunity in the absence of a primary antibody response.

39 : Safety and immunogenicity of a prototype adjuvanted inactivated split-virus influenza A (H5N1) vaccine in infants and children.

40 : Safety and immunogenicity of a vero cell culture-derived whole-virus influenza A(H5N1) vaccine in a pediatric population.

41 : Safety, Tolerability and Immunogenicity of an MF59-adjuvanted, Cell Culture-derived, A/H5N1, Subunit Influenza Virus Vaccine: Results From a Dose-finding Clinical Trial in Healthy Pediatric Subjects.

42 : AS03B-adjuvanted H5N1 influenza vaccine in children 6 months through 17 years of age: a phase 2/3 randomized, placebo-controlled, observer-blinded trial.

43 : A recombinant viruslike particle influenza A (H7N9) vaccine.

44 : H7N9 live attenuated influenza vaccine in healthy adults: a randomised, double-blind, placebo-controlled, phase 1 trial.

45 : Serological responses to an avian influenza A/H7N9 vaccine mixed at the point-of-use with MF59 adjuvant: a randomized clinical trial.

46 : Immunogenicity and Safety of an AS03-Adjuvanted H7N9 Pandemic Influenza Vaccine in a Randomized Trial in Healthy Adults.

47 : Immunogenicity and Safety of an AS03-Adjuvanted H7N9 Pandemic Influenza Vaccine in a Randomized Trial in Healthy Adults.

48 : One health, many interpretations: vaccinating risk groups against H5 avian influenza in Finland.

49 : Immunogenicity and safety of AS03A-adjuvanted H5N1 influenza vaccine prepared from bulk antigen after stockpiling for 4 years.

50 : Safety and immunogenicity of influenza A(H5N1) vaccine stored up to twelve years in the National Pre-Pandemic Influenza Vaccine Stockpile (NPIVS).