Longitudinal Analysis of Neuraminidase and Hemagglutinin Antibodies to Influenza A Viruses after Immunization with Seasonal Inactivated Influenza Vaccines
Abstract
:1. Introduction
2. Materials and Methods
2.1. Vaccines
2.2. Study Design
2.3. Hemagglutination Inhibition Assay
2.4. Influenza Viruses
2.5. Enzyme-Linked Lectin Assay (ELLA)
2.6. NA Activity of Influenza Viruses and Influenza Vaccines
2.7. Statistical Analysis
2.8. Study Limitations
3. Results
3.1. Antibody Levels throughout the Year after Vaccination
3.2. Antibody Seroconversion Rates after Vaccination
3.3. Preexisting Immunity Impact and Correlation Analysis of HI and NI Antibody Titers
3.4. Neuraminidase Functional Activity in the Vaccine Formulation
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Appendix A
Response→ | HI seroconversion | NI seroconversion | ||
Factor ↓ | H1 | H3 | N1 | N2 |
Titer at day 0 | p = 0.0009 *** | p = 0.0268 * | p = 0.0914 | p = 0.0522 |
Vaccine type | p = 0.7699 | p = 0.5658 | p = 0.0031 ** | p = 0.1097 |
Age | p = 0.5432 | p = 0.5389 | p = 0.8303 | p = 0.7365 |
Sex | p = 0.0511 | p = 0.8002 | p = 0.7034 | p = 0.1209 |
References
- Dhanasekaran, V.; Sullivan, S.; Edwards, K.M.; Xie, R.; Khvorov, A.; Valkenburg, S.A.; Cowling, B.J.; Barr, I.G. Human seasonal influenza under COVID-19 and the potential consequences of influenza lineage elimination. Nat. Commun. 2022, 13, 1721. [Google Scholar] [CrossRef] [PubMed]
- Ambrose, C.S.; Levin, M.J. The rationale for quadrivalent influenza vaccines. Hum. Vaccines Immunother. 2012, 8, 81–88. [Google Scholar] [CrossRef] [PubMed]
- Lavanchy, D.; Osterhaus, A.D. Recommendations for the use of inactivated influenza vaccines and other preventive measures. Vaccine 2001, 19, 1849–1853. [Google Scholar] [CrossRef]
- Kon, T.C.; Onu, A.; Berbecila, L.; Lupulescu, E.; Ghiorgisor, A.; Kersten, G.F.; Cui, Y.-Q.; Amorij, J.-P.; Van der Pol, L. Influenza vaccine manufacturing: Effect of inactivation, splitting and site of manufacturing. Comparison of influenza vaccine production processes. PLoS ONE 2016, 11, e0150700. [Google Scholar] [CrossRef] [PubMed]
- Hendriks, J.; Holleman, M.; de Boer, O.; de Jong, P.; Luytjes, W. An international technology platform for influenza vaccines. Vaccine 2011, 29, A8–A11. [Google Scholar] [CrossRef]
- Iorio, A.M.; Rivosecchi, P.; Zei, T.; Neri, M.; Merletti, L. Immune response to trivalent inactivated influenza vaccine in young and elderly subjects. Vaccine 1989, 7, 341–344. [Google Scholar] [CrossRef]
- World Health Organization. Influenza vaccines: Recommendations for the use of inactivated influenza vaccines and other preventive measures. Wkly. Epidemiol. Rec. = Relev. Épidémiologiquehebdomadaire 2000, 75, 281–288. [Google Scholar]
- Tregoning, J.S.; Russell, R.F.; Kinnear, E. Adjuvanted influenza vaccines. Hum. Vaccines Immunother. 2018, 14, 550–564. [Google Scholar] [CrossRef]
- Bright, R.A.; Neuzil, K.M.; Pervikov, Y.; Palkonyay, L. WHO meeting on the role of neuraminidase in inducing protective immunity against influenza infection, Vilamoura, Portugal, September 14, 2008. Vaccine 2009, 27, 6366–6369. [Google Scholar] [CrossRef]
- Krammer, F.; Fouchier, R.A.M.; Eichelberger, M.C.; Webby, R.J.; Shaw-Saliba, K.; Wan, H.; Wilson, P.C.; Compans, R.W.; Skountzou, I.; Monto, A.S. NAction! How can neuraminidase-based immunity contribute to better influenza virus vaccines? mBio 2018, 9, 10–1128. [Google Scholar] [CrossRef]
- Giurgea, L.T.; Morens, D.M.; Taubenberger, J.K.; Memoli, M.J. Influenza neuraminidase: A neglected protein and its potential for a better influenza vaccine. Vaccines 2020, 8, 409. [Google Scholar] [CrossRef] [PubMed]
- Krammer, F.; Palese, P. Advances in the development of influenza virus vaccines. Nat. Rev. Drug Discov. 2015, 14, 167–182. [Google Scholar] [CrossRef] [PubMed]
- Maier, H.E.; Nachbagauer, R.; Kuan, G.; Ng, S.; Lopez, R.; Sanchez, N.; Stadlbauer, D.; Gresh, L.; Schiller, A.; Rajabhathor, A.; et al. Pre-existing antineuraminidase antibodies are associated with shortened duration of influenza A (H1N1) pdm virus shedding and illness in naturally infected adults. Clin. Infect. Dis. 2020, 70, 2290–2297. [Google Scholar] [CrossRef]
- McCullers, J.A.; Huber, V.C. Correlates of vaccine protection from influenza and its complications. Hum. Vaccines Immunother. 2012, 8, 34–44. [Google Scholar] [CrossRef] [PubMed]
- Weiss, C.D.; Wang, W.; Lu, Y.; Billings, M.; Eick-Cost, A.; Couzens, L.; Sanchez, J.L.; Hawksworth, A.W.; Seguin, P.; Myers, C.A.; et al. Neutralizing and neuraminidase antibodies correlate with protection against influenza during a late season A/H3N2 outbreak among unvaccinated military recruits. Clin. Infect. Dis. 2020, 71, 3096–3102. [Google Scholar] [CrossRef]
- Wei, C.J.; Crank, M.C.; Shiver, J.; Graham, B.S.; Mascola, J.R.; Nabel, G.J. Next-generation influenza vaccines: Opportunities and challenges. Nat. Rev. Drug Discov. 2020, 19, 239–252. [Google Scholar] [CrossRef]
- Eichelberger, M.C.; Monto, A.S. Neuraminidase, the forgotten surface antigen, emerges as an influenza vaccine target for broadened protection. J. Infect. Dis. 2019, 219 (Suppl. S1), S75–S80. [Google Scholar] [CrossRef]
- World Health Organization. Recommended Composition of Influenza Virus Vaccines for Use in the 2018–2019 Northern Hemisphere Influenza Season. 2018. Available online: https://www.who.int/publications/m/item/recommended-composition-of-influenza-virus-vaccines-for-use-in-the-2018-2019-northern-hemisphere-influenza-season (accessed on 6 November 2023).
- Erofeeva, M.K.; Nickonorov, I.J.; Maksakova, V.L.; Stukova, M.A.; Konshina, O.S.; Okhapkina, E.A.; Voicehovskaya, E.M.; Korovkin, S.A.; Melnikhov, S.J.; Kiselev, O.I. Protective properties of inactivated virosomal influenza vaccine. Procedia Vaccinol. 2014, 8, 24–33. [Google Scholar] [CrossRef]
- Talayev, V.; Zaichenko, I.; Svetlova, M.; Matveichev, A.; Babaykina, O.; Voronina, E.; Mironov, A. Low-dose influenza vaccine Grippol Quadrivalent with adjuvant Polyoxidonium induces a T helper-2 mediated humoral immune response and increases NK cell activity. Vaccine 2020, 38, 6645–6655. [Google Scholar] [CrossRef]
- Erofeeva, M.K.; Stukova, M.A.; Shakhlanskaya, E.V.; Buzitskaya, Z.V.; Maksakova, V.L.; Krainova, T.I.; Pisareva, M.M.; Popov, A.B.; Pozdnjakova, M.G.; Lioznov, D.A. Evaluation of the Preventive Effectiveness of Influenza Vaccines in the Epidemic Season 2019–2020 in St. Petersburg. Epidemiol. Vaccinal Prev. 2021, 20, 52–60. [Google Scholar] [CrossRef]
- World Health Organization. Manual for the Laboratory Diagnosis and Virological Surveillance of Influenza. 2.F Serological Diagnosis of Influenza by Haemagglutination Inhibition Testing. 2011. Available online: https://apps.who.int/iris/handle/10665/44518 (accessed on 6 November 2023).
- Desheva, Y.; Smolonogina, T.; Sychev, I.; Rekstin, A.; Ilyushina, N.; Lugovtsev, V.; Samsonova, A.; Go, A.; Lerner, A. Anti-neuraminidase antibodies against pandemic A/H1N1 influenza viruses in healthy and influenza-infected individuals. PLoS ONE 2018, 13, e0196771. [Google Scholar] [CrossRef] [PubMed]
- Committee for Medicinal Products for Human Use. Note for Guidance on Harmonisation of Requirements for Influenza Vaccines; European Agency for the Evaluation of Medicinal Products: Brussels, Belgium, 1997. [Google Scholar]
- Rajendran, M.; Nachbagauer, R.; Ermler, M.E.; Bunduc, P.; Amanat, F.; Izikson, R.; Cox, M.; Palese, P.; Eichelberger, M.; Krammer, F. Analysis of anti-influenza virus neuraminidase antibodies in children, adults, and the elderly by ELISA and enzyme inhibition: Evidence for original antigenic sin. mBio 2017, 8, e02281-16. [Google Scholar] [CrossRef] [PubMed]
- Marcelin, G.; Sandbulte, M.R.; Webby, R.J. Contribution of antibody production against neuraminidase to the protection afforded by influenza vaccines. Rev. Med. Virol. 2012, 22, 267–279. [Google Scholar] [CrossRef] [PubMed]
- Halbherr, S.J.; Ludersdorfer, T.H.; Ricklin, M.; Locher, S.; Berger Rentsch, M.; Summerfield, A.; Zimmer, G. Biological and protective properties of immune sera directed to the influenza virus neuraminidase. J. Virol. 2015, 89, 1550–1563. [Google Scholar] [CrossRef]
- Rajendran, M.; Krammer, F.; McMahon, M. The human antibody response to the influenza virus neuraminidase following infection or vaccination. Vaccines 2021, 9, 846. [Google Scholar] [CrossRef]
- Su, B.; Wurtzer, S.; Rameix-Welti, M.A.; Dwyer, D.; van der Werf, S.; Naffakh, N.; Clavel, F.; Labrosse, B. Enhancement of the influenza A hemagglutinin (HA)-mediated cell-cell fusion and virus entry by the viral neuraminidase (NA). PLoS ONE 2009, 4, e8495. [Google Scholar] [CrossRef]
- Wohlbold, T.J.; Podolsky, K.A.; Chromikova, V.; Kirkpatrick, E.; Falconieri, V.; Meade, P.; Amanat, F.; Tan, J.; tenOever, B.R.; Tan, G.S.; et al. Broadly protective murine monoclonal antibodies against influenza B virus target highly conserved neuraminidase epitopes. Nat. Microbiol. 2017, 2, 1415–1424. [Google Scholar] [CrossRef]
- Gao, R.; Sheng, Z.; Sreenivasan, C.C.; Wang, D.; Li, F. Influenza A virus antibodies with antibody-dependent cellular cytotoxicity function. Viruses 2020, 12, 276. [Google Scholar] [CrossRef]
- Pliasas, V.C.; Menne, Z.; Aida, V.; Yin, J.H.; Naskou, M.C.; Neasham, P.J.; North, J.F.; Wilson, D.; Horzmann, K.A.; Jacob, J.; et al. A Novel Neuraminidase Virus-Like Particle Vaccine Offers Protection against Heterologous H3N2 Influenza Virus Infection in the Porcine Model. Front. Immunol. 2022, 13, 915364. [Google Scholar] [CrossRef]
- Desheva, Y.; Petkova, N.; Losev, I.; Guzhov, D.; Go, A.; Chao, Y.C.; Tsai, C.H. Establishment of a Pseudovirus Platform for Neuraminidase Inhibiting Antibody Analysis. Int. J. Mol. Sci. 2023, 24, 2376. [Google Scholar] [CrossRef]
- Desheva, Y.; Losev, I.; Petkova, N.; Kudar, P.; Donina, S.; Mamontov, A.; Tsai, C.H.; Chao, Y.C. Antigenic Characterization of Neuraminidase of Influenza A/H7N9 Viruses Isolated in Different Years. Pharmaceuticals 2022, 15, 1127. [Google Scholar] [CrossRef] [PubMed]
- Monto, A.S.; Petrie, J.G.; Cross, R.T.; Johnson, E.; Liu, M.; Zhong, W.; Levine, M.; Katz, J.M.; Ohmit, S.E. Antibody to Influenza Virus Neuraminidase: An Independent Correlate of Protection. J. Infect. Dis. 2015, 212, 1191–1199. [Google Scholar] [CrossRef] [PubMed]
- Chen, Y.Q.; Wohlbold, T.J.; Zheng, N.Y.; Huang, M.; Huang, Y.; Neu, K.E.; Lee, J.; Wan, H.; Rojas, K.T.; Kirkpatrick, E.; et al. Influenza Infection in Humans Induces Broadly Cross-Reactive and Protective Neuraminidase-Reactive Antibodies. Cell 2018, 173, 417–429. [Google Scholar] [CrossRef] [PubMed]
- Powers, D.C.; Kilbourne, E.D.; Johansson, B.E. Neuraminidase-Specific Antibody Responses to Inactivated Influenza Virus Vaccine in Young and Elderly Adults. Clin. Diagn. Lab. Immunol. 1996, 3, 511–516. [Google Scholar] [CrossRef]
- Cate, T.R.; Rayford, Y.; Niño, D.; Winokur, P.; Brady, R.; Belshe, R.; Chen, W.; Atmar, R.L.; Couch, R.B. A high dosage influenza vaccine induced significantly more neuraminidase antibody than standard vaccine among elderly subjects. Vaccine 2010, 28, 2076–2079. [Google Scholar] [CrossRef]
- Couch, R.B.; Atmar, R.L.; Keitel, W.A.; Quarles, J.M.; Wells, J.; Arden, N.; Niño, D. Randomized Comparative Study of the Serum Antihemagglutinin and Antineuraminidase Antibody Responses to Six Licensed Trivalent Influenza Vaccines. Vaccine 2012, 31, 190–195. [Google Scholar] [CrossRef]
- Ito, H.; Nishimura, H.; Kisu, T.; Hagiwara, H.; Watanabe, O.; Kadji, F.M.N.; Sato, K.; Omiya, S.; Takashita, E.; Nobusawa, E. Low Response in Eliciting Neuraminidase Inhibition Activity of Sera among Recipients of a Split, Monovalent Pandemic Influenza Vaccine During the 2009 Pandemic. PLoS ONE 2020, 15, e0233001. [Google Scholar] [CrossRef]
- Sultana, I.; Yang, K.; Getie-Kebtie, M.; Couzens, L.; Markoff, L.; Alterman, M.; Eichelberger, M.C. Stability of neuraminidase in inactivated influenza vaccines. Vaccine 2014, 32, 2225–2230. [Google Scholar] [CrossRef]
- Shanko, A.; Shuklina, M.; Kovaleva, A.; Zabrodskaya, Y.; Vidyaeva, I.; Shaldzhyan, A.; Fadeev, A.; Korotkov, A.; Zaitceva, M.; Stepanova, L.; et al. Comparative immunological study in mice of inactivated influenza vaccines used in the Russian immunization program. Vaccines 2020, 8, 756. [Google Scholar] [CrossRef]
- Johansson, B.E.; Moran, T.M.; Kilbourne, E.D. Antigen-presenting B cells and helper T cells cooperatively mediate intravirionic antigenic competition between influenza A virus surface glycoproteins. Proc. Natl. Acad. Sci. USA 1987, 84, 6869–6873. [Google Scholar] [CrossRef]
- Couch, R.B.; Atmar, R.L.; Franco, L.M.; Quarles, J.M.; Wells, J.; Arden, N.; Niño, D.; Belmont, J.W. Antibody correlates and predictors of immunity to naturally occurring influenza in humans and the importance of antibody to the neuraminidase. J. Infect. Dis. 2013, 207, 974–981. [Google Scholar] [CrossRef] [PubMed]
- Gilbert, P.B.; Fong, Y.; Juraska, M.; Carpp, L.N.; Monto, A.S.; Martin, E.T.; Petrie, J.G. HAI and NAI titer correlates of inactivated and live attenuated influenza vaccine efficacy. BMC Infect. Dis. 2019, 19, 1–12. [Google Scholar] [CrossRef] [PubMed]
- Auladell, M.; Phuong, H.V.M.; Mai, L.T.Q.; Tseng, Y.Y.; Carolan, L.; Wilks, S.; Thai, P.Q.; Price, D.; Duong, N.T.; Hang, N.L.K.; et al. Influenza virus infection history shapes antibody responses to influenza vaccination. Nat. Med. 2022, 28, 363–372. [Google Scholar] [CrossRef] [PubMed]
- Wan, H.; Gao, J.; Yang, H.; Yang, S.; Harvey, R.; Chen, Y.Q.; Zheng, N.Y.; Chang, J.; Carney, P.J.; Li, X.; et al. The neuraminidase of A (H3N2) influenza viruses circulating since 2016 is antigenically distinct from the A/Hong Kong/4801/2014 vaccine strain. Nat. Microbiol. 2019, 4, 2216–2225. [Google Scholar] [CrossRef]
- Powell, H.; Pekosz, A. Neuraminidase antigenic drift of H3N2 clade 3c. 2a viruses alters virus replication, enzymatic activity and inhibitory antibody binding. PLoS Pathog. 2020, 16, e1008411. [Google Scholar] [CrossRef]
- Creytens, S.; Pascha, M.N.; Ballegeer, M.; Saelens, X.; de Haan, C.A.M. Influenza neuraminidase characteristics and potential as a vaccine target. Front. Immunol. 2021, 12, 786617. [Google Scholar] [CrossRef] [PubMed]
Vaccine Type | Split (n = 27) | Subunit-Adjuvanted (n = 46) |
---|---|---|
Vaccine (n) | Ultrix (n = 27) | Sovigripp (n =19) Grippol plus (n = 27) |
Age group | ||
18–60, n (%) | 13 (48%) | 33 (72%) |
>60, n (%) | 14 (52%) | 13 (28%) |
Age—years Median (IQR) | ||
18–60 | 39 (32–42) | 37 (34–48) |
>60 | 65 (61–67) | 72 (66–79) |
Sex | ||
Female, n (%) | 22 (81%) | 31 (67%) |
Male, n (%) | 5 (19%) | 15 (33%) |
Seronegative, HA * | ||
H1N1pdm09, n (%) | 4 (15%) | 13 (28%) |
H3N2, n (%) | 5 (19%) | 18 (39%) |
Seronegative, NA ** | ||
H1N1pdm09, n (%) | 12 (44%) | 29 (63%) |
H3N2, n (%) | 18 (67%) | 24 (52%) |
Assay | Subtype | Split (n = 27) | Subunit-Adjuvanted (n = 46) | ||
---|---|---|---|---|---|
Percent | 95%CI | Percent | 95%CI | ||
HI test | H1 | 44 | (25–64) | 57 | (42–72) |
H3 | 67 | (46–84) | 54 | (39–69) | |
ELLA | N1 | 74 * | (54–89) | 37 * | (23–53) |
N2 | 59 | (39–77) | 39 | (25–54) |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Sergeeva, M.V.; Romanovskaya-Romanko, E.A.; Krivitskaya, V.Z.; Kudar, P.A.; Petkova, N.N.; Kudria, K.S.; Lioznov, D.A.; Stukova, M.A.; Desheva, Y.A. Longitudinal Analysis of Neuraminidase and Hemagglutinin Antibodies to Influenza A Viruses after Immunization with Seasonal Inactivated Influenza Vaccines. Vaccines 2023, 11, 1731. https://doi.org/10.3390/vaccines11111731
Sergeeva MV, Romanovskaya-Romanko EA, Krivitskaya VZ, Kudar PA, Petkova NN, Kudria KS, Lioznov DA, Stukova MA, Desheva YA. Longitudinal Analysis of Neuraminidase and Hemagglutinin Antibodies to Influenza A Viruses after Immunization with Seasonal Inactivated Influenza Vaccines. Vaccines. 2023; 11(11):1731. https://doi.org/10.3390/vaccines11111731
Chicago/Turabian StyleSergeeva, Mariia V., Ekaterina A. Romanovskaya-Romanko, Vera Z. Krivitskaya, Polina A. Kudar, Nadezhda N. Petkova, Kira S. Kudria, Dmitry A. Lioznov, Marina A. Stukova, and Yulia A. Desheva. 2023. "Longitudinal Analysis of Neuraminidase and Hemagglutinin Antibodies to Influenza A Viruses after Immunization with Seasonal Inactivated Influenza Vaccines" Vaccines 11, no. 11: 1731. https://doi.org/10.3390/vaccines11111731