#18,410
We've a cautionary report today in NPJ Vaccines which dives deeply into issues we've looked at many times before; the double-edged sword of poultry vaccination against bird flu. In this case, the LPAI H9N2 virus, which - despite 30 years of vaccination campaigns - remains ubiquitous in Chinese poultry.
While originally relegated pretty much to Asia, over the past 15 years we've seen H9N2 expand to the Middle East and into the African Continent (see Viruses: A Global Perspective on H9N2 Avian Influenza Virus).
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Range Of Endemic H9N2 Viruses |
While admittedly not at the very top of our list of pandemic concerns, the CDC has 2 different lineages (A(H9N2) G1 and A(H9N2) Y280) on their short list of influenza viruses with zoonotic potential (see CDC IRAT SCORE), and several candidate vaccines have been developed.
In 2021's J. Virus Erad.: Ineffective Control Of LPAI H9N2 By Inactivated Poultry Vaccines - China, we looked at a report which found the inactivated virus vaccines used by China against H9N2 to be no match for this rapidly evolving pathogen.
They wrote:The failure of vaccination might be because of inefficient application, low dose, and low vaccination coverage (especially in the household sector).11,12 Moreover, the continuing transmission in combination with the intensive long-term usage of the inactivated virus vaccine may have led to antigenic changes leading to immune escape.
While China's 2017 H5+H7 Poultry Vaccination campaign is rightfully credited with halting their H7N9 epidemic, and (at least temporarily) reducing their burden of HPAI H5, they have seen a rebound in H5 cases in recent years.
Other vaccination campaigns have yielded far-less positive results, with ineffective vaccines only masking infection symptoms, while allowing the virus to continue to spread and evolve. A few (of many) reports include:
- In 2012's Egypt: A Paltry Poultry Vaccine, researchers examined the effectiveness of six commercially available H5 poultry vaccines used in Egypt and found only one actually appeared to offer protection.
- Six years later, another study (see Sci. Reports: Efficacy Of AI Vaccines Against The H5N8 Virus in Egypt) found `. . . most of the commercial poultry H5 vaccines used in the present study were ineffective. . . '
- More recently, in 2023's WUR: 2 of 4 H5 Poultry Vaccines Tested Appear Effective Against H5N1, found ineffective vaccines were still being marketed.
Today's study is based on H9N2, although some parallels can likely be drawn with vaccination against other subtypes.
The gist of this report is that inactivated vaccines have failed to prevent - or even reduce - H9N2 in China's poultry, and may have driven viral evolution (including mammalian adaptations). This is a lengthy and detailed report, and so I've only posted some highlights.
Follow the link to read it in its entirety. I'll have a postscript after the break.
Impact of inactivated vaccine on transmission and evolution of H9N2 avian influenza virus in chickens
Zhe Hu, Hui Ai, Zhen Wang, Shiyue Huang, Honglei Sun, Xinxin Xuan, Mingyue Chen, Jinxiu Wang, Wei Yan, Jiayi Sun, Juan Pu, Christopher B. Brooke, Kin-Chow Chang, Yipeng Sun & Jinhua Liu
npj Vaccines volume 10, Article number: 67 (2025) Cite this article
Abstract
H9N2 avian influenza virus (AIV) is endemic in poultry worldwide and increasingly zoonotic. Despite the long-term widespread use of inactivated vaccines, H9N2 AIVs remain dominant in chicken flocks. We demonstrated that inactivated vaccines did not prevent the replication of H9N2 AIVs in the upper airway of vaccinated chickens. Viral transmission was enhanced during sequential passage in vaccinated chickens, which was attributed to the restricted production of defective interfering particles and the introduction of stable mutations (NP-N417D, M1-V219I, and NS1-R140W) which enhanced viral replication.
Notably, the genetic diversity of H9N2 AIVs was greater and included more potential mammal/human-adapted mutations after passage through vaccinated chickens than through naïve chickens, which might facilitate the emergence of mammal-adapted strains. By contrast, vaccines inducing cellular/mucosal immunity in the upper respiratory tract effectively limit H9N2 AIV. These findings highlight the limitations of inactivated vaccines and the need for revised vaccination strategies to control H9N2 AIV.
(SNIP)
Discussion
The control of H9N2 AIVs in chickens is essential to mitigate against disease outbreaks in birds and the emergence of novel zoonotic AIVs. However, the long-term use of H9N2 inactivated vaccines has not reduced the prevalence of H9N2 AIVs in chickens38. On the contrary, the replication of the H9N2 virus has seemingly increased in chickens and mammalian species20,39.
In the present study, we found that the use of an inactivated H9N2 vaccine did not prevent or reduce virus shedding, but selected for viral strains with increased replication ability and restricted DIP production, thus facilitating the transmission of H9N2 AIVs in vaccinated chickens. The transmission of H9N2 AIV in vaccinated chickens introduces a further problem in that it increases the diversity of viral genes in the circulating virus, possibly generating more novel strains. Therefore, a policy review is urgently required, together with changes in the current use of inactivated H9N2 viral vaccines in poultry.
Although H9N2 AIVs do not exhibit antigenic drift as significantly as H5 or H7 AIVs in clinic, the emergence of H9N2 variants belonging to novel antigenic group has been shown to reduce the efficacy of inactivated vaccines40,41. More importantly, in this study, we found that the H9 AIV subtype has a greater capacity for replication in the upper respiratory tract than subtype H5 or H7. However, in chickens vaccinated with the H9N2 inactivated vaccine, the IgG antibody levels in the lavage fluid from the upper respiratory tract were only 3.65% of those detected in the blood. Therefore, the humoral immune response induced by the inactivated vaccine in the upper respiratory tract is insufficient to neutralize the H9N2 virus, with its high replication level, at this site. This may explain why H9N2 continues to spread in vaccinated flocks. In contrast, rHVT-H9, which also induces a cellular immune response, and H9N2-LAIV, which induces both a cellular immune response and a local mucosal immune response in the upper respiratory tract, efficiently prevented H9N2 AIV replication in chickens. A similar phenomenon has also been observed for the SARS-CoV-2 virus (responsible for COVID-19). Although vaccines have been effective in reducing the severity and mortality rate of SARS-CoV-2 virus infections, these vaccines do not effectively prevent viral replication and transmission in the upper respiratory tract42,43,44. However, live vector vaccines, which elicit strong cellular immunity, and vaccines that induce local mucosal immunity are effective in blocking the replication and/or transmission of multiple SARS-CoV-2 variants in the respiratory tract45,46. Therefore, inactivated vaccines are insufficient for the effective control of viruses that replicate efficiently in the upper respiratory tract.
Our study demonstrates that vaccines capable of inducing cellular immunity and/or local mucosal immunity in the upper respiratory tract, such as rHVT-H9 and live attenuated vaccines, exhibit enhanced protective efficacy against H9N2 infection in chickens. We previously demonstrated that rHVT-H9, which can be used in chicken embryos or in 1-day-old chickens, effectively circumvented interference from maternal antibodies in the field47. Furthermore, the fact that only a single dose is required for rHVT-H9 simplifies the vaccination process and reduces costs. A major challenge in HVT vaccine development is inserting multiple foreign genes without affecting the replication of recombinant HVT. Since the influenza virus genome is segmented, the potential risk of reassortment between live attenuated vaccine and wild-type virus remains a concern. A recent study proposes a strategy for targeted genomic rearrangement to prevent the recombination of specific viral RNA segments48. Although there are currently no commercial vaccines inducing cellular immunity or upper respiratory mucosal immunity against H9N2 AIV, awareness of the limitations of inactivated vaccines could accelerate the development and application of such vaccines.
(SNIP)
In this study, we found that the genetic diversity of H9N2 in the vaccinated group was higher than naïve group and there were more previously reported mammalian-adaptive mutations observed in the viruses in vaccinated group. Meanwhile, there were more monoclonal viruses in vaccinated chickens, which exhibited enhanced replication and pathogenicity in mice. These findings suggest that, when vaccines fail to completely prevent viral shedding and transmission, the diverse progeny viruses might pose a potential risk of cross-species transmission. However, it should be noted that the frequencies of most mammalian adapted mutations in our study are below 10%, and the role of these mutations in mammalian adaptation should be further validated. Moreover, it remains uncertain whether viral adaptation in mice fully reflects the situation in humans.
Notably, the long-term and widespread use of inactivated vaccines in China has failed to control H9N2, and H9N2 has even become the predominant subtype in poultry, along with an increased number of human H9N2 cases4,12. Additionally, enhanced mammalian adaptability has been observed in recent strains39. Attention needs to be paid to whether the failure of vaccine immunization against H9N2 AIV might increase the viral threat to public health.
In the present study, viral populations isolated from vaccinated chickens showed greater genetic diversity and the accumulation of mutations that improved their fitness. Because the presently used inactivated H9N2 vaccine is ineffective, and in the face of the continued increase in the replication ability and potential antigenic variation of H9N2 AIVs in chickens39,59, the current vaccination policy for the control of the H9N2 virus requires urgent review. The need to develop vaccines against H9N2 AIV that induce cellular immunity and/or mucosal immunity in the upper respiratory airway cannot be overemphasized. The development of multivalent rHVT vaccines and the improvement of live attenuated vaccine safety represent key directions for future vaccine research. Additionally, the combined use of antiviral drugs could improve the effectiveness of H9N2 prevention and control.
Desperate farmers, beleaguered politicians, and shell-shocked consumers are all looking for ways to reduce the burden of avian flu, and poultry vaccination is certainly an attractive option. But the devil is always in the details.
We need improved (and continually updated) vaccines, ways to ensure they are being properly and consistently applied, and greatly enhanced surveillance and testing of vaccinated flocks (looking for asymptomatic breakthrough infections).
None of this will be cheap, or easy. But going with anything less risks making a bad situation much worse in the long run.