Avian influenza is currently a major animal health concern worldwide. It is a zoonotic disease that spread among wild/domestic birds and mammals (terrestrial or aquatic), including cattle, and humans (1, 2). The virus is highly contagious and is transmitted between infectious and susceptible animals, principally via the respiratory route, therefore it is considered a mandatory notification sickness by the Word Organization for Animal Health (WOAH).

The severity of the clinical effects usually varies according to the type of virus-those with low pathogenicity result in low mortality rates, while the highly pathogenic ones can cross the respiratory and intestinal barriers, spread through the bloodstream, damage all tissues, and lead to high mortality rates (3–5). In all cases, vaccines are considered as additional preventive tools to limit the spread of the virus, reduce the severity of the disease, reduce the morbidity rate during outbreaks, improve the recovery of the sick animal and reduce the significant damage it causes, including zoonotic damage (6, 7).

Anti-influenza immunopreventive formulations have some limitations, such as the low capacity for generating cross-immunity and effectiveness dependent on the antigenic closeness between circulating and vaccine strains (8). The uncertainty regarding this last aspect is based on the abrupt genetic and antigenic changes of the etiological agent, caused by its ability to replicate without mutation protection mechanisms and by the recombination of genomes between strains (9–11). The hemagglutinin and neuraminidase contributes to this problem (12, 13), as subtle changes in the amino acids in its structure can lead to the emergence of new lineages, with renewed capacity to cross the barrier between species (10, 14, 15), and escape the defense of the host. These frequent mutations of the virus are the main limiting factor for the development of an effective vaccination (16).

Many companies and governments are considering research and development of veterinary vaccines against avian influenza type A despite these difficulties (17). Although this official projection can achieve technological sovereignty and self-sufficiency of vaccination programs, it also requires strategies to produce safe, effective, and stable high-yielding vaccines with high yields (18). Therefore, the WOAH has made recommendations to interested nations (19), providing access to production technology adaptable to their epidemiological realities (20). However, all the information mentioned is not sufficient to achieve success, as it is necessary to know the scientific-commercial environment surrounding these vaccines, the emerging production technologies, and the new diversity of adjuvants (21).

Unfortunately, this knowledge is often unavailable to researchers and entrepreneurs as it is dispersed among various scientific fields and is not very attainable. In view of these difficulties, technological surveillance studies are a useful tool for obtaining, concentrating and analyzing existing scientific-technological knowledge, understanding the global commercial environment and facilitating strategic decision-making in the industrial sector. Based on this, the present study aimed to identify research, production technology and commercial trends of veterinary vaccines against avian influenza A in farm animals and pets during the period 2019–2023 globally.

This study was descriptive in nature, employing a methodology that combines qualitative and quantitative methods. It involved retrospective bibliometric research covering the last 5 years (2019–2023), along with additional cross-sectional market studies conducted in 2023. The study was conducted from September to November 2023, and in no case was the use of experimental animals required.

The present academic-commercial analysis of veterinary vaccines against avian influenza confirms that the disease is a priority for the veterinary sector (24). It shows the key role of classical vaccines in reduce the virus shedding in the animal population (25), despite doubts about their efficacy (short-lived immunity), the inability to induce sterilizing immunity and the complications of their use in epidemiological surveillance (7, 8, 26). In this endeavor, science and the veterinary biopharmaceutical industry converge on the same path: inactivated virus vaccine. This common position may be associated to the less clinical signs, less degree of pathological lesions and lower titer of viral excretion observed in birds vaccinated with this type of vaccine (25, 27, 28) and to its rapid development-production.

The popularity achieved by this type of production technology is also supported by decades of application with excellent results and the possibility of each country possibility to manufacture its own formulations from national isolates (24). In this context, classical autogenous vaccines have the advantages of adapting to local health needs, accelerating the response to new influenza subtypes in the field, avoiding vaccinating with outdated strains, achieving national self-sufficiency and low sales prices per dose, and avoiding excessive costs related to long transport times (29, 30). For these reasons, it is expected that science will continue to update local vaccine strains (31) to manufacture and test new inactivated vaccines for chickens/ducks (32), pigs (33) and companion animals (34), depending on the epidemiological conditions in different countries.

The evidence gathered in this research also shows that recombinant vaccines against influenza are the second-best solution studied and marketed globally during the period 2019–2023 to immunoprotect productive species. Such a stance coincides with scientific advances on molecular mechanisms of genomic replication (35), characterization of conserved and variable sites of the viral RNA (36), and, in particular, the expression of hemagglutinin and/or neuraminidase genes in avian smallpox, turkey herpesvirus, Newcastle virus, Escherichia coli, and plants (Nicotiana benthamiana) (37–40). This latter alternative approach offers significant advantages associated with the ability to grow the plants on a large scale, rapid and efficient production in required quantities, low costs (40) and thermostability of the antigen (39). However, like other vaccines, it does not overcome the challenge of cross-protection and the high risk of occupational exposure from handling the avian influenza antigen remains. The introduction of these plant species for vaccine production requires improved technologies both to minimize the alkaloid (toxic substance) content and to increase the antigen yield. It also requires confined cultivation systems to avoid the possibility of agrochemical contamination, adverse weather conditions, irregular soil composition and pathogen attack (40).

The low presence of modern vaccines (n = 16) in the product catalogs issued by the companies studied (n = 136), allows inferring that much of the new scientific knowledge remains in the exploratory field, and few are converted into marketable products. Consequently, the role of these formulations in global veterinary health management during the 2019–2023 period remains limited. Changing this reality in the future involves obtaining vaccines capable of effectively stopping virus replication and excretion and generating specific antibodies that do not interfere with the diagnosis of naturally infected animals. Although some progress has been made in this regard (41–43), much work remains to be done; it is necessary to surpass the indicators of safety, efficacy and duration of immunity achieved by traditional vaccines in the field, demonstrate the stability of the synthetic antigen and explore the use of the mucosa (buccal, nasal and ocular) as routes of administration for different animal species.

The need to optimize the efficacy of inactivated vaccines and, the development of new purified, synthetic or recombinant antigens that are specific and well characterized but not very immunogenic, explains, at least in part, the great scientific interest in developing new and potent adjuvants that help to increase the immune response, in addition to generating a rapid decrease in clinical signs (44). The academic projection shown in Figure 1 involves aluminum nanoparticles composed of quaternized chitosan (45), different fractions of purified saponins (46), and natural oils of plant origin (47), among other novel compounds. However, it is expected that the introduction of academic advances into industrial practice will require time and significant financial resources. Its delayed implementation is associated not only with the diversity of animal species with different immune systems but also with delays in the development of economical, and robust formulations (low toxicity, generate a potent immune response, optimum antigen adsorption-dsorption capacity, biodegradable, and stable under normal storage conditions) that comply with good production practices (48, 49). Despite this, the industry remains very attentive to the evaluation of these substances because their incorporation has many advantages: optimization of the immunogenic efficacy of current vaccines, increase the immune response at mucosal level without the need for injection, production of larger quantities of doses with fewer antigens, and reduction of production costs without sacrificing the quality of the vaccine (47).

Another coincidental feature identified in this study is the dominance of avian, and swine vaccines both in scientific articles and in the market. This occurrence, although observed in a previous study on veterinary infectious diseases (23), and confirms once again that science and industry continue to focus on the immunoprotection of fundamental species in the production of animal protein for the human consumption, promoting the livelihood of rural poor, especially in underdeveloped countries, and supporting national food security (30).

Together with the identification of common interests between science and industry, divergent thematic areas were also found. In the first case, there was no correspondence between the high number of co-occurrences identified in the bibliometric study (n = 720) and the scarce presence of live vaccines in the market (0.7%, 1/136, Flu Avert®, H3N8). This fact suggests that science insists on achieving modified live strains (less virulent or avirulent) despite serious safety issues in clinical use and cumbersome manufacturing processes. This research may be encouraged by the fact that these are the only vaccines that best mimic natural infection, thus inducing strong humoral and cellular immunity. Several attenuation options have been explored, such as degradation of viral proteins (50), deletion of the NS1 gene encoding non-structural protein 1, or point mutations in the haemagglutinin gene (51–55). Although the results are successful in generating robust humoral, mucosal and cellular immunity against homologous and heterologous viruses, the resulting genetic constructs have not progressed beyond the scientific frontier. These options have yet to overcome numerous regulatory barriers and to implement new vaccination strategies involving the simultaneous use of live and inactivated vaccines.

In the second case, the numerous co-ocurrent publications on canine vaccination against avian influenza (n = 510) and the poor presence of commercial vaccines may be related to the gradual changes taking place in our societies regarding pet ownership and care. The loss of traditional pet functions such as protection, hunting and defense to contemporary functions such as companionship and provision of affection (56, 57) encourages pet adoption, cohabitation in smaller spaces and sharing of pathogens. The increased likelihood of zoonotic events, coupled with frequent reports of influenza infections of various subtypes in dogs (58), raise new concerns that necessitate further research into immunoprotection. However, this scientific interest has not yet translated into vaccine production, and dogs are the least represented species in the global market, with only 4.5% of commercial vaccines available in 2023.

The final area of divergence identified in this study concerns equine vaccines. In this respect, little scientific interest in research into new equine flu vaccines was observed (n = 19), despite the fact that equine flu is a species of great military, cultural, genetic, sporting, recreational and economic value. This reality is contradicted by the large number of commercial vaccines available on the world market (34.5%, 47/136), being the second most immunoprotected animal species. This imbalance between science and industry is difficult to explain considering the great usefulness of the horse for humans since ancient times (transportation, agricultural and livestock work, meat, milk, hair, and leather) and the great impact of the disease on the equine industry (compulsory health declaration, low sporting performance and restrictions on international trade) (59, 60).

With respect to the significant genetic diversity of influenza strains (high and low pathogenicity subtypes) involved in research and commercial vaccine production was an expected occurrence, given the extensive antigenic variants observed in wild strains (61). Consequently, it is not coincidental to find close links between the field strains with the highest global circulation and vaccine strains (62), in particular those with a high capacity to rapidly spread between migratory birds, domestic birds, mammals and humans such as H3Nx, and H5Nx. The industrial use of numerous lineages responsible for outbreaks in Africa, Asia, America and Europe is extremely important to increase the effectiveness of disease prevention and control programs in countries that practice vaccination and reduce the frequency of animals with severe forms of the disease (63–65).

The unstable health situation associated with the constant genetic evolution of the pathogen, the increasing number of affected species and the ‘One Health’ approach will encourage the veterinary and human scientific and industrial communities to continue their collaboration. Unity of public and private interests will be imperative not only for effective, coordinated and sustained epidemiological surveillance and reporting actions worldwide, but also for rapid dissemination of knowledge on new influenza A virus sequences and outbreaks, in order to prevent possible future pandemics (66, 67).

The positive impact observed in those countries that decided to implement massive vaccination (66), may change in the future. The rapid antigenic evolution of the virus, chemical instability of hemagglutinin/neuraminidase, and wide range of susceptible and transmitting hosts make it almost impossible to predict the subtype of the next pandemic virus and, therefore, the existence of an adequate vaccine (12, 67). Faced with these questions, science is attempting to design so-called “universal vaccines” that include several subtypes of influenza in the same formulation. In this regard, in vivo tests using H1N9/H3N8/H5N1/H7N3 mixtures yield satisfactory results; however, there is still a long way to go (68). The efficacy and safety of these vaccines depend on many factors: antigenic match of vaccine strains to circulating strains, manufacturing procedures, adjuvants, antigen concentration, dosage and method of administration (69). Therefore, these formulations cannot be expected to be applied in daily clinical practice in the short term, which justifies their peripheral position observed in Figure 1. The success of this new immunoprotective option is closely linked to the union of public and private interests. The resulting alliance will allow not only effective, coordinated and sustained epidemiological surveillance, but also rapid dissemination of emerging epidemic strain sequences for inclusion in new formulations (70, 71).

The extensive network of academic journals publishing veterinary scientific results on avian influenza, the significant participation of countries in joint research (Figure 2) and the large number of commercial vaccines worldwide (Table 2) reveal a reality: scientists, vaccine manufacturers and farmers are jointly searching for answers to defeat the same adversary. All, from different approaches, identify this virus as a major threat to the security of nations and urgently need to reduce the serious health and economic impacts that the disease can cause (increased mortality, reduced production and trade restrictions) (72). The high international priority given to this virus (7, 8) may have been an element promoting the balance observed between academic and industrial production of veterinary vaccines in some of the countries involved in this study, such as the United States, Vietnam, Iran, Spain, Germany, Russia, the Netherlands, and Egypt.

This heterogeneity is due to the wide geographical distribution of the disease, its great epidemiological complexity, the increasing number of affected species (1, 2), the experience in research, development and application of vaccines that some countries possess (73), as well as the existence of an economic cooperation framework that prioritizes cross-border research between developing nations and high-income international scientific institutions (74). In this context, the prominent presence of the United States and China coincides with the largest epidemic events reported globally and therefore, they are the most interested in collaborating with other nations to mitigate zoonotic risks and the resulting economic and trade impacts (62, 64). For these reasons, they dedicate significant research funds resulting in a high volume of publications and international collaborations, as illustrated in Figure 3 (75).

The commercial interest of pharmaceutical companies in introducing influenza vaccines combined with antigens from different subtypes (18.4%, 25/136), viruses, and bacterias (52.2%, 71/136) to the market arises from multiple reasons. These include extending protection against several subtypes in a single administration (76), preventing a greater number of diseases per dose, rapid compliance with the vaccination schedule, and increased immunization coverage. Other elements favoring the presence of these formulations on the world market are the constant emergence of antibiotic-resistant bacterial strains (77), co-circulation of different pathogens in the same population, reduced costs in application, transportation, and storage of biological material as well as decreased stress in animals due to less manipulation (78). Therefore, these formulations are highly appreciated by animal health professionals and prove highly useful in the case of avian influenza. Recent evidence confirms that this pathogen has the capacity to co-infect animals, increasing the frequency and severity of respiratory tract lesions (79). Based on this evidence, combination vaccines emerge as an appropriate solution, eliciting a rapid and improved immune response in both avian and equine species compared to monovalent vaccines against Newcastle and herpesvirus types 1 and 4 (24, 80, 81).

This study has several limitations in its implementation. First, Scopus was the sole database consulted, and only articles written in English were considered. This could potentially lead to an underestimation of the available information, as other important databases and languages used to communicate scientific findings were not included. However, these decisions were made considering that Scopus constitutes the largest database of peer-reviewed scientific literature globally (22) and that the main international journals (Q1 and Q2) exclusively accept articles in English (70, 71, 82). Additionally, articles written in other languages (Spanish, Portuguese, French, German, Russian, and Chinese, among others) tend to receive fewer citations, despite being indexed in international databases (83). Second, the bibliometric search may have overestimated the productivity of certain countries because the primary authors’ affiliation does not always reflect their true institution of origin or the place where the research was conducted. Third, by analyzing 24 companies from 17 countries, it was possible to exclude others of regional importance, thus potentially causing biases or data omissions.

However, the results shown include formulations from the largest commercial players in the global veterinary biopharmaceutical sector, such as Boehringer Ingelheim, Elanco, MSD Animal Health, and Zoetis. Despite all these limitations, the study can be used to identify global trends in veterinary biopharmaceutical science and industry for preventing avian influenza. Furthermore, it can serve as a starting point for future research on this topic, involving similar or different productive and affective species, thereby addressing the identified limitations.

The study demonstrated the fundamental role of classical production methods (based on the use of the whole pathogen) in avian influenza A research and the production of veterinary vaccines.