Hemagglutinin head-specific responses dominate over stem-specific responses following prime boost with mismatched vaccines

Jegaskanda, Sinthujan; Andrews, Sarah F.; Wheatley, Adam K.; Yewdell, Jonathan W.; McDermott, Adrian B.; Subbarao, Kanta

doi:10.1172/jci.insight.129035

Cited by 17 publications

(13 citation statements)

References 45 publications

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“…Inferred germline antibodies or unmutated common ancestors (UCAs) of broadly neutralizing influenza HA antibodies isolated from human donors show high affinity for strains circulating during the donor's early childhood, suggesting that early exposures imprint responses that are subsequently matured and refined upon re-exposure [195][196][197] . Repeated exposure in the form of seasonal vaccination against influenza does not appear to alter the patterns of dominance established towards particular HA subtypes 175,[198][199][200] . However, recall and maturation of HA stemdirected responses has been observed following immunization with divergent wild-type or chimeric strains, where the stem region is the conserved epitope between exposures [201][202][203][204][205] .…”

Section: Increasing the Breadth Of Antibody Responsesmentioning

confidence: 90%

Protein engineering strategies for rational immunogen design

Caradonna

Schmidt

2021

npj Vaccines

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Antibody immunodominance refers to the preferential and asymmetric elicitation of antibodies against specific epitopes on a complex protein antigen. Traditional vaccination approaches for rapidly evolving pathogens have had limited success in part because of this phenomenon, as elicited antibodies preferentially target highly variable regions of antigens, and thus do not confer long lasting protection. While antibodies targeting functionally conserved epitopes have the potential to be broadly protective, they often make up a minority of the overall repertoire. Here, we discuss recent protein engineering strategies used to favorably alter patterns of immunodominance, and selectively focus antibody responses toward broadly protective epitopes in the pursuit of next-generation vaccines for rapidly evolving pathogens.

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Section: Increasing the Breadth Of Antibody Responsesmentioning

confidence: 90%

Protein engineering strategies for rational immunogen design

Caradonna

Schmidt

2021

npj Vaccines

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“…21,39 ). Despite the fact that NHPs were capable of generating human-like bnAb responses to either group 1 or group 2 HA stem following infection or vaccination 16,[40][41][42] , there are no bnAbs that broadly neutralize both group 1 and group 2 influenza viruses reported to date. In the present study, we identified the NHP bnAb 789-203-3C12 as the first example of such cross-group bnAbs.…”

Section: Discussionmentioning

confidence: 99%

Vaccine-elicitation of cross-group neutralizing protective antibodies to influenza A viruses

Moin

Boyington

Boyoglu-Barnum

et al. 2022

Preprint

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Current influenza vaccines predominantly induce immunity to the hypervariable viral hemagglutinin (HA) head, requiring frequent vaccine reformulation. Conversely, antigenic sites on the conserved HA stem are subdominant and harbor a supersite which is targeted by broadly neutralizing antibodies (bnAbs), making it a prime target for universal vaccines. Here, we show that co-immunization of two stem immunogens derived from influenza A group 1 and 2 HAs elicits cross-group protective immunity and neutralizing antibody responses in mice, ferrets, and nonhuman primates (NHPs). Immunized mice were protected from multiple group 1 and 2 viruses, and all animal models showed broad serum neutralizing activity. A bnAb isolated from an immunized NHP broadly neutralized and conferred protection from viruses including H5N1 and H7N9. Genetic and structural analyses revealed a remarkable convergent evolution between macaque and human bnAbs, illustrating the biophysical constraints for acquiring immunoglobulins with cross-group specificity. Co-immunization of stem immunogens elicits not only group-specific protective immunity, but also cross-group bnAb responses, and represents a step towards broadly protective influenza vaccines.

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“…As previously stated, conventional vaccines elicit largely strain-specific humoral immune responses predominantly focused on the antigenically variable HA head domain. The immunosubdominance , or poor immunogenicity of the HA stalk in this context is well documented (i.e., head > stalk) ( 136 ). However, advances in innovative HA immunogen design in recent years has enabled re-focusing of humoral immune responses towards this immunosubdominant HA stalk domain.…”

Section: Antigen Targets For Avian Influenza Vaccine Developmentmentioning

confidence: 99%

Adenoviral Vectors as Vaccines for Emerging Avian Influenza Viruses

et al. 2021

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It is evident that the emergence of infectious diseases, which have the potential for spillover from animal reservoirs, pose an ongoing threat to global health. Zoonotic transmission events have increased in frequency in recent decades due to changes in human behavior, including increased international travel, the wildlife trade, deforestation, and the intensification of farming practices to meet demand for meat consumption. Influenza A viruses (IAV) possess a number of features which make them a pandemic threat and a major concern for human health. Their segmented genome and error-prone process of replication can lead to the emergence of novel reassortant viruses, for which the human population are immunologically naïve. In addition, the ability for IAVs to infect aquatic birds and domestic animals, as well as humans, increases the likelihood for reassortment and the subsequent emergence of novel viruses. Sporadic spillover events in the past few decades have resulted in human infections with highly pathogenic avian influenza (HPAI) viruses, with high mortality. The application of conventional vaccine platforms used for the prevention of seasonal influenza viruses, such as inactivated influenza vaccines (IIVs) or live-attenuated influenza vaccines (LAIVs), in the development of vaccines for HPAI viruses is fraught with challenges. These issues are associated with manufacturing under enhanced biosafety containment, and difficulties in propagating HPAI viruses in embryonated eggs, due to their propensity for lethality in eggs. Overcoming manufacturing hurdles through the use of safer backbones, such as low pathogenicity avian influenza viruses (LPAI), can also be a challenge if incompatible with master strain viruses. Non-replicating adenoviral (Ad) vectors offer a number of advantages for the development of vaccines against HPAI viruses. Their genome is stable and permits the insertion of HPAI virus antigens (Ag), which are expressed in vivo following vaccination. Therefore, their manufacture does not require enhanced biosafety facilities or procedures and is egg-independent. Importantly, Ad vaccines have an exemplary safety and immunogenicity profile in numerous human clinical trials, and can be thermostabilized for stockpiling and pandemic preparedness. This review will discuss the status of Ad-based vaccines designed to protect against avian influenza viruses with pandemic potential.

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Hemagglutinin head-specific responses dominate over stem-specific responses following prime boost with mismatched vaccines

Cited by 17 publications

References 45 publications

Protein engineering strategies for rational immunogen design

Protein engineering strategies for rational immunogen design

Vaccine-elicitation of cross-group neutralizing protective antibodies to influenza A viruses

Adenoviral Vectors as Vaccines for Emerging Avian Influenza Viruses

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