Prospects and Challenges in the Development of Universal Influenza Vaccines

Current influenza vaccines offer suboptimal protection and depend on annual reformulation and yearly administration. Vaccine technology has rapidly advanced during the last decade, facilitating development of next-generation influenza vaccines that can target a broader range of influenza viruses. The development and licensure of a universal influenza vaccine could provide a game changing option for the control of influenza by protecting against all influenza A and B viruses. Here we review important findings and considerations regarding the development of universal influenza vaccines and what we can learn from this moving forward with a SARS-CoV-2 vaccine design.

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Design, synthesis and primary immunologic evaluation of M2e-CRM197 conjugate as a universal influenza vaccine candidate

Current Pharmaceutical Biotechnology ◽

10.2174/1389201021666201104145006 ◽

2020 ◽

Vol 21 ◽

Author(s):

Lu Xu ◽

Chun Zhang ◽

Jing Zhang ◽

Rong Yu ◽

Zhiguo Su

Keyword(s):

Immune Responses ◽

Influenza Vaccine ◽

Influenza A Virus ◽

Influenza A ◽

Vaccine Development ◽

Acute Infection ◽

Acid Hydrazide ◽

Influenza Viruses ◽

Carrier Protein ◽

Universal Influenza Vaccine

Background: Influenza is a contagious respiratory illness caused by acute infection of influenza viruses, among which influenza A virus causes epidemic seasonal infection nearly every year. Along with unpredictability of evolving influenza A virus and time-consuming vaccine development cycles, novel universal influenza vaccine designed to induce broadly cross-reactive immune responses against frequently mutant influenza A virus strains are greatly urgent. Objective: The aim of this study was to synthesize a novel vaccine through the dual-site specific conjugation of the constant epitope of 23 amino acids (M2e) of influenza A virus with highly immunogenic carrier protein of cross-reacting material (CRM197) under denaturation, and evaluate its primary immunogenicity in mice. Methods: The antigen (M2e) and the carrier protein (CRM197) were linked with different type of hetero-functionalized linkers, α-maleimide-ε-hydrazide polyethylene glycol 2k (MAL-PEG-HZ) and N-β-maleimidopropionic acid hydrazide (BMPH) separately. The immunogenicity of the M2e-CRM197 conjugates with different type of linkers was evaluated in mice, and the M2e-specific total IgG and IgG-isotypes were determined by ELSIA. Results: Immunogenicity study revealed that anti-M2e antibody could be induced by the conjugate products, M2e-PEGCRM197 and M2e-BMPH-CRM197, were approximately 30 and 90-fold higher than that of M2e group. In addition, the antiM2e antibody level induced by M2e-PEG-CRM197 conjugate was three times higher than that of M2e-BMPH-CRM197 conjugate, and the former could simultaneously activate both cellar and humoral immune responses. Conclusions: The M2e-CRM197 conjugated vaccines we synthesized in this study are highly immunogenic compared with M2e alone. Besides, evidences were presented here indicated that the hydrophilic, non-immunogenic and biocompatible chain of the cross-linker might be a better choice for development of conjugate vaccine.

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A Live Attenuated Influenza Vaccine Elicits Enhanced Heterologous Protection When the Internal Genes of the Vaccine Are Matched to Those of the Challenge Virus

Journal of Virology ◽

10.1128/jvi.01065-19 ◽

2019 ◽

Vol 94 (4) ◽

Cited By ~ 3

Author(s):

Andrew Smith ◽

Laura Rodriguez ◽

Maya El Ghouayel ◽

Aitor Nogales ◽

Jeffrey M. Chamberlain ◽

...

Keyword(s):

Influenza Vaccine ◽

Influenza A ◽

H1n1 Virus ◽

Influenza Infection ◽

Influenza Viruses ◽

Influenza Vaccines ◽

Temperature Sensitive ◽

Live Attenuated Influenza Vaccine ◽

Cell Immunity

ABSTRACT Influenza A virus (IAV) causes significant morbidity and mortality, despite the availability of viral vaccines. The efficacy of live attenuated influenza vaccines (LAIVs) has been especially poor in recent years. One potential reason is that the master donor virus (MDV), on which all LAIVs are based, contains either the internal genes of the 1960 A/Ann Arbor/6/60 or the 1957 A/Leningrad/17/57 H2N2 viruses (i.e., they diverge considerably from currently circulating strains). We previously showed that introduction of the temperature-sensitive (ts) residue signature of the AA/60 MDV into a 2009 pandemic A/California/04/09 H1N1 virus (Cal/09) results in only 10-fold in vivo attenuation in mice. We have previously shown that the ts residue signature of the Russian A/Leningrad/17/57 H2N2 LAIV (Len LAIV) more robustly attenuates the prototypical A/Puerto Rico/8/1934 (PR8) H1N1 virus. In this work, we therefore introduced the ts signature from Len LAIV into Cal/09. This new Cal/09 LAIV is ts in vitro, highly attenuated (att) in mice, and protects from a lethal homologous challenge. In addition, when our Cal/09 LAIV with PR8 hemagglutinin and neuraminidase was used to vaccinate mice, it provided enhanced protection against a wild-type Cal/09 challenge relative to a PR8 LAIV with the same attenuating mutations. These findings suggest it may be possible to improve the efficacy of LAIVs by better matching the sequence of the MDV to currently circulating strains. IMPORTANCE Seasonal influenza infection remains a major cause of disease and death, underscoring the need for improved vaccines. Among current influenza vaccines, the live attenuated influenza vaccine (LAIV) is unique in its ability to elicit T-cell immunity to the conserved internal proteins of the virus. Despite this, LAIV has shown limited efficacy in recent years. One possible reason is that the conserved, internal genes of all current LAIVs derive from virus strains that were isolated between 1957 and 1960 and that, as a result, do not resemble currently circulating influenza viruses. We have therefore developed and tested a new LAIV, based on a currently circulating pandemic strain of influenza. Our results show that this new LAIV elicits improved protective immunity compared to a more conventional LAIV.

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Cross-Reactive Neuraminidase-Inhibiting Antibodies Elicited by Immunization with Recombinant Neuraminidase Proteins of H5N1 and Pandemic H1N1 Influenza A Viruses

Journal of Virology ◽

10.1128/jvi.00585-15 ◽

2015 ◽

Vol 89 (14) ◽

pp. 7224-7234 ◽

Cited By ~ 31

Author(s):

Wen-Chun Liu ◽

Chia-Ying Lin ◽

Yung-Ta Tsou ◽

Jia-Tsrong Jan ◽

Suh-Chin Wu

Keyword(s):

Influenza Virus ◽

Sialic Acid ◽

Influenza Vaccine ◽

Influenza A ◽

Expression System ◽

Influenza Viruses ◽

Pandemic H1n1 ◽

Influenza A Viruses ◽

Homologous Virus ◽

Universal Influenza Vaccine

ABSTRACTNeuraminidase (NA), an influenza virus envelope glycoprotein, removes sialic acid from receptors for virus release from infected cells. For this study, we used a baculovirus-insect cell expression system to construct and purify recombinant NA (rNA) proteins of H5N1 (A/Vietnam/1203/2004) and pandemic H1N1 (pH1N1) (A/Texas/05/2009) influenza viruses. BALB/c mice immunized with these proteins had high titers of NA-specific IgG and NA-inhibiting (NI) antibodies against H5N1, pH1N1, H3N2, and H7N9 viruses. H5N1 rNA immunization resulted in higher quantities of NA-specific antibody-secreting B cells against H5N1 and heterologous pH1N1 viruses in the spleen. H5N1 rNA and pH1N1 rNA immunizations both provided complete protection against homologous virus challenges, with H5N1 rNA immunization providing better protection against pH1N1 virus challenges. Cross-reactive NI antibodies were further dissected via pH1N1 rNA protein immunizations with I149V (NA with a change of Ile to Val at position 149), N344Y, and I365T/S366N NA mutations. The I365T/S366N mutation of pH1N1 rNA enhanced cross-reactive NI antibodies against H5N1, H3N2, and H7N9 viruses. It is our hope that these findings provide useful information for the development of an NA-based universal influenza vaccine.IMPORTANCENeuraminidase (NA) is an influenza virus enzymatic protein that cleaves sialic acid linkages on infected cell surfaces, thus facilitating viral release and contributing to viral transmission and mucus infection. In currently available inactivated or live, attenuated influenza vaccines based on the antigenic content of hemagglutinin proteins, vaccine efficacy can be contributed partly through NA-elicited immune responses. We investigated the NA immunity of different recombinant NA (rNA) proteins associated with pH1N1 and H5N1 viruses. Our results indicate that H5N1 rNA immunization induced more potent cross-protective immunity than pH1N1 rNA immunization, and three mutated residues, I149V, I365T, and S366N, near the NA enzyme active site(s) are linked to enhanced cross-reactive NA-inhibiting antibodies against heterologous and heterosubtypic influenza A viruses. These findings provide useful information for the development of an NA-based universal influenza vaccine.

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Exploring the Potential of T-Cells for a Universal Influenza Vaccine

Vaccines ◽

10.3390/vaccines8040598 ◽

2020 ◽

Vol 8 (4) ◽

pp. 598

Author(s):

Sharon Vijayanand ◽

Keegan Braz Gomes ◽

Rikhav P. Gala ◽

Mohammad N. Uddin ◽

Martin J. D’Souza

Keyword(s):

T Cells ◽

Influenza Vaccine ◽

Influenza A ◽

Influenza Viruses ◽

Seasonal Epidemics ◽

Universal Influenza Vaccine

Among the four types of influenza viruses, the influenza A strains and their subtypes have been responsible for causing worldwide pandemics and seasonal epidemics [...]

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Development of Universal Influenza Vaccines Targeting Conserved Viral Proteins

Vaccines ◽

10.3390/vaccines7040169 ◽

2019 ◽

Vol 7 (4) ◽

pp. 169 ◽

Cited By ~ 8

Author(s):

Jazayeri ◽

Poh

Keyword(s):

Immune Responses ◽

Influenza Vaccine ◽

Neutralizing Antibodies ◽

Influenza Viruses ◽

Surface Proteins ◽

Influenza Vaccines ◽

Influenza Pandemics ◽

Host Immune Responses ◽

Production Platform ◽

Universal Influenza Vaccine

Vaccination is still the most efficient way to prevent an infection with influenza viruses. Nevertheless, existing commercial vaccines face serious limitations such as availability during epidemic outbreaks and their efficacy. Existing seasonal influenza vaccines mostly induce antibody responses to the surface proteins of influenza viruses, which frequently change due to antigenic shift and or drift, thus allowing influenza viruses to avoid neutralizing antibodies. Hence, influenza vaccines need a yearly formulation to protect against new seasonal viruses. A broadly protective or universal influenza vaccine must induce effective humoral as well as cellular immunity against conserved influenza antigens, offer good protection against influenza pandemics, be safe, and have a fast production platform. Nanotechnology has great potential to improve vaccine delivery, immunogenicity, and host immune responses. As new strains of human epidemic influenza virus strains could originate from poultry and swine viruses, development of a new universal influenza vaccine will require the immune responses to be directed against viruses from different hosts. This review discusses how the new vaccine platforms and nanoparticles can be beneficial in the development of a broadly protective, universal influenza vaccine.

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M2e-based universal influenza vaccines: a historical overview and new approaches to development

Journal of Biomedical Science ◽

10.1186/s12929-019-0572-3 ◽

2019 ◽

Vol 26 (1) ◽

Cited By ~ 15

Author(s):

Daria Mezhenskaya ◽

Irina Isakova-Sivak ◽

Larisa Rudenko

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Influenza Infection ◽

Influenza Viruses ◽

Influenza Vaccines ◽

Effective Vaccine ◽

Historical Overview ◽

M2 Protein ◽

Random Intervals ◽

Universal Influenza Vaccine

Abstract The influenza A virus was isolated for the first time in 1931, and the first attempts to develop a vaccine against the virus began soon afterwards. In addition to causing seasonal epidemics, influenza viruses can cause pandemics at random intervals, which are very hard to predict. Vaccination is the most effective way of preventing the spread of influenza infection. However, seasonal vaccination is ineffective against pandemic influenza viruses because of antigenic differences, and it takes approximately six months from isolation of a new virus to develop an effective vaccine. One of the possible ways to fight the emergence of pandemics may be by using a new type of vaccine, with a long and broad spectrum of action. The extracellular domain of the M2 protein (M2e) of influenza A virus is a conservative region, and an attractive target for a universal influenza vaccine. This review gives a historical overview of the study of M2 protein, and summarizes the latest developments in the preparation of M2e-based universal influenza vaccines.

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Influenza Vaccines toward Universality through Nanoplatforms and Given by Microneedle Patches

Viruses ◽

10.3390/v12111212 ◽

2020 ◽

Vol 12 (11) ◽

pp. 1212

Author(s):

Sijia Tang ◽

Wandi Zhu ◽

Bao-Zhong Wang

Keyword(s):

Public Health ◽

Influenza Vaccine ◽

Seasonal Influenza ◽

Surface Antigens ◽

Influenza Viruses ◽

Influenza Vaccines ◽

Vaccine Strategy ◽

Influenza Pandemics ◽

Major Surface ◽

Universal Influenza Vaccine

Influenza is one of the top threats to public health. The best strategy to prevent influenza is vaccination. Because of the antigenic changes in the major surface antigens of influenza viruses, current seasonal influenza vaccines need to be updated every year to match the circulating strains and are suboptimal for protection. Furthermore, seasonal vaccines do not protect against potential influenza pandemics. A universal influenza vaccine will eliminate the threat of both influenza epidemics and pandemics. Due to the massive challenge in realizing influenza vaccine universality, a single vaccine strategy cannot meet the need. A comprehensive approach that integrates advances in immunogen designs, vaccine and adjuvant nanoplatforms, and vaccine delivery and controlled release has the potential to achieve an effective universal influenza vaccine. This review will summarize the advances in the research and development of an affordable universal influenza vaccine.

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New Technologies for Influenza Vaccines

Microorganisms ◽

10.3390/microorganisms8111745 ◽

2020 ◽

Vol 8 (11) ◽

pp. 1745

Author(s):

Steven Rockman ◽

Karen L. Laurie ◽

Simone Parkes ◽

Adam Wheatley ◽

Ian G. Barr

Keyword(s):

Computational Biology ◽

Influenza Vaccine ◽

New Technologies ◽

Vaccine Development ◽

Influenza Vaccines ◽

Lead Times ◽

Next Generation ◽

Development Cycle ◽

Universal Influenza Vaccine

Vaccine development has been hampered by the long lead times and the high cost required to reach the market. The 2020 pandemic, caused by a new coronavirus (SARS-CoV-2) that was first reported in late 2019, has seen unprecedented rapid activity to generate a vaccine, which belies the traditional vaccine development cycle. Critically, much of this progress has been leveraged off existing technologies, many of which had their beginnings in influenza vaccine development. This commentary outlines the most promising of the next generation of non-egg-based influenza vaccines including new manufacturing platforms, structure-based antigen design/computational biology, protein-based vaccines including recombinant technologies, nanoparticles, gene- and vector-based technologies, as well as an update on activities around a universal influenza vaccine.

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Elicitation of broadly protective immunity to influenza by multivalent hemagglutinin nanoparticle vaccines

10.1101/2020.05.30.125179 ◽

2020 ◽

Cited By ~ 5

Author(s):

Seyhan Boyoglu-Barnum ◽

Daniel Ellis ◽

Rebecca A. Gillespie ◽

Geoffrey B. Hutchinson ◽

Young-Jun Park ◽

...

Keyword(s):

Influenza Vaccine ◽

Neutralizing Antibodies ◽

Protective Immunity ◽

Neutralizing Antibody ◽

Influenza Viruses ◽

Antibody Responses ◽

Influenza Vaccines ◽

Next Generation ◽

Protective Antibody

AbstractInfluenza vaccines that confer broad and durable protection against diverse virus strains would have a major impact on global health. However, next-generation vaccine design efforts have been complicated by challenges including the genetic plasticity of the virus and the immunodominance of certain epitopes in its glycoprotein antigens. Here we show that computationally designed, two-component nanoparticle immunogens induce potently neutralizing and broadly protective antibody responses against a wide variety of influenza viruses. The nanoparticle immunogens display 20 hemagglutinin (HA) trimers in a highly immunogenic array, and their assembly in vitro enables precisely controlled co-display of multiple distinct HAs in defined ratios. Nanoparticle immunogens displaying the four HAs of licensed quadrivalent influenza vaccines (QIV) elicited hemagglutination inhibition and neutralizing antibody responses to vaccine-matched strains that were equivalent or superior to commercial QIV in mice, ferrets, and nonhuman primates. The nanoparticle immunogens—but not QIV—simultaneously induced broadly protective antibody responses to heterologous viruses, including H5N1 and H7N9, by targeting the subdominant yet conserved HA stem. Unlike previously reported influenza vaccine candidates, our nanoparticle immunogens can alter the intrinsic immunodominance hierarchy of HA to induce both potent receptor-blocking and broadly cross-reactive stem-directed antibody responses and are attractive candidates for a next-generation influenza vaccine that could replace current seasonal vaccines.One Sentence SummaryNanoparticle immunogens displaying four seasonal influenza hemagglutinins elicit neutralizing antibodies directed at both the immunodominant head and the conserved stem and confer broad protective immunity.

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Next generation methodology for updating HA vaccines against emerging human seasonal influenza A(H3N2) viruses

Scientific Reports ◽

10.1038/s41598-020-79590-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

James D. Allen ◽

Ted M. Ross

Keyword(s):

Influenza Virus ◽

Immune Responses ◽

Influenza A ◽

Seasonal Influenza ◽

Influenza Viruses ◽

Next Generation ◽

Virus Infections ◽

Wild Type ◽

Influenza Hemagglutinin ◽

H3n2 Influenza

AbstractWhile vaccines remain the best tool for preventing influenza virus infections, they have demonstrated low to moderate effectiveness in recent years. Seasonal influenza vaccines typically consist of wild-type influenza A and B viruses that are limited in their ability to elicit protective immune responses against co-circulating influenza virus variant strains. Improved influenza virus vaccines need to elicit protective immune responses against multiple influenza virus drift variants within each season. Broadly reactive vaccine candidates potentially provide a solution to this problem, but their efficacy may begin to wane as influenza viruses naturally mutate through processes that mediates drift. Thus, it is necessary to develop a method that commercial vaccine manufacturers can use to update broadly reactive vaccine antigens to better protect against future and currently circulating viral variants. Building upon the COBRA technology, nine next-generation H3N2 influenza hemagglutinin (HA) vaccines were designed using a next generation algorithm and design methodology. These next-generation broadly reactive COBRA H3 HA vaccines were superior to wild-type HA vaccines at eliciting antibodies with high HAI activity against a panel of historical and co-circulating H3N2 influenza viruses isolated over the last 15 years, as well as the ability to neutralize future emerging H3N2 isolates.

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