Engineered Nanoparticulate Vaccines to Combat Recurring and Pandemic Influenza Threats

Abstract

Influenza is one of the most severe and contagious respiratory infectious diseases. Influenza virus infection causes annual epidemics and occasional pandemics, resulting in an enormous health and economic burden worldwide. During the 2019-2020 flu season, the centers for disease control and prevention (CDC) estimates that flu caused 38 million illnesses, including 18 million medical visits, 405 000 hospitalizations, and 22 000 deaths in the United States. [1] Influenza viruses are enveloped RNA viruses of the Orthomyxoviridae family. Because the RNA polymerases lack the proofreading function, influenza viruses undergo constant antigenic drift and shift within animal and human reservoirs. [2] Influenza A viruses (IAVs) and influenza B viruses (IBVs) are the main circulating viruses that affect human health. So far, 18 hemagglutinin (HA) subtypes belonging to two HA phylogenetic groups and 11 neuraminidase (NA) subtypes have been identified for IAVs. [3] The IAVs H1N1 and H3N2 currently cause most epidemic diseases in humans. IBVs form a single antigenic group with two distinct lineages: Victoria and Yamagata.Seasonal vaccination is the most cost-effective method to combat influenza infection. However, current seasonal flu vaccines induce strain-specific immunity that rapidly wanes and displays low efficiencies against mismatched circulating strains and no effect on pandemics. The vaccines need annual reformulation based on the prediction by the WHO Global Influenza Surveillance and Response System to counter antigenic variations. [4] This uncertainty makes mismatches occur, resulting in suboptimal immunity. Fewer influenza cases occurred in the past 2020-2021 flu season in the United States than in any on record, [5] probably due to the widespread use of face masks and social distance to control COVID-19. The lack of exposure to the flu may make the population more susceptible to the virus when it returns. [6] Parallelly, predicting which strains will be circulating in the upcoming flu season and selecting vaccine manufacturing will be more challenging than ever.A next-generation universal influenza vaccine that elicits long-lasting cross-protective immunity against variant influenza strains will overcome the limitations of the current flu v accines. [7,8] Nanotechnology plays an indispensable role in the development of such vaccines. [9][10][11] Influenza viruses are nanosized particles enveloped by lipid membranes inserted with surface glycoprotein spikes. Nanoparticle vaccines can optimally mimic the influenza virus nanostructure with high antigen loads, facilitate targeted delivery and controlled antigen release, and synergize with molecular adjuvants to improve vaccine potency and breadth. Moreover, nanoparticle vaccines can facilitate rapid and scalable production, minimize cold-chain dependence, incorporate antigens in a flexibly modular fashion, and be affordably produced. Up to date, a variety of nanoparticle formulations have shown promising results in generating cross-reactive influenza immunity.

Enhancing cross-protection against influenza by heterologous sequential immunization with mRNA LNP and protein nanoparticle vaccines

“…Including conserved antigens is a common strategy in the development of universal influenza vaccines 3 , 4 , and some pioneering candidates have advanced to clinical trials 5 . However, the protection efficacy of these vaccines is not ideal due to the inherently poor immunogenicity of the highly conserved antigens.…”

“…Different vaccine formulations can elicit distinct immune responses depending on antigen types, delivery platforms, and administration routes 4 , 9 . Protein-based subunit vaccines typically evoke strong antibody responses but poor cellular responses 10 .…”