The poor performance of 2014-15 Northern Hemisphere (NH) influenza vaccines was attributed to mismatched H3N2 component with circulating epidemic strains. Using human serum samples collected from 2009-10, 2010-11 and 2014-15 NH influenza vaccine trials, we assessed their cross-reactive hemagglutination inhibition (HAI) antibody responses against recent H3 epidemic isolates. All three populations (children, adults, and older adults) vaccinated with the 2014-15 NH egg- or cell-based vaccine, showed >50% reduction in HAI post-vaccination geometric mean titers against epidemic H3 isolates from those against egg-grown H3 vaccine strain A/Texas/50/2012 (TX/12e). The 2014-15 NH vaccines, regardless of production type, failed to further extend HAI cross-reactivity against H3 epidemic strains from previous seasonal vaccines. Head-to-head comparison between ferret and human antisera derived antigenic maps revealed different antigenic patterns among representative egg- and cell-grown H3 viruses characterized. Molecular modeling indicated that the mutations of epidemic H3 strains were mainly located in antibody-binding sites A and B as compared with TX/12e. To improve vaccine strain selection, human serologic testing on vaccination-induced cross-reactivity need be emphasized along with virus antigenic characterization by ferret model.

/pdf/h3n2-mismatch-of-2014-15-northern-hemisphere-influenza-4wom1agssq.pdf

H3N2 Mismatch of 2014–15 Northern Hemisphere Influenza Vaccines and Head-to-head Comparison between Human and Ferret Antisera derived Antigenic Maps

Pseudoviruses are useful surrogates for highly pathogenic viruses because of their safety, genetic stability, and scalability for screening assays. Many different pseudovirus platforms exist, each with different advantages and limitations. Here we report our efforts to optimize and characterize an HIV-based lentiviral pseudovirus assay for screening neutralizing antibodies for SARS-CoV-2 using a stable 293T cell line expressing human angiotensin converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). We assessed different target cells, established conditions that generate readouts over at least a two-log range, and confirmed consistent neutralization titers over a range of pseudovirus input. Using reference sera and plasma panels, we evaluated assay precision and showed that our neutralization titers correlate well with results reported in other assays. Overall, our lentiviral assay is relatively simple, scalable, and suitable for a variety of SARS-CoV-2 entry and neutralization screening assays.

/pdf/establishment-of-a-well-characterized-sars-cov-2-lentiviral-25mcnr0tgm.pdf

Establishment of a well-characterized SARS-CoV-2 lentiviral pseudovirus neutralization assay using 293T cells with stable expression of ACE2 and TMPRSS2.

Rapid antigenic shift and drift of influenza A viruses (IAVs) result in annual epidemics and periodic pandemics that place a major strain on global healthcare systems and pose a significant threat to the global economy [1]. Recent work has focused on characterizing a new class of IAV antibodies that bind to the hemagglutinin (HA) stalk domain [2–11]. These antibodies typically exhibit much broader reactivity and neutralizing activity than antibodies that bind to conventional antigenic sites on the HA head. HA stalk antibodies are thought to be boosted most efficiently in the context of infection when individuals are exposed to HAs whose head domains differ substantially from previous exposures, but whose stalk domains remain conserved [12]. We have recently postulated that the elicitation of such antibodies may have contributed to the extinction of seasonal IAV strains [12]. Indeed, we have demonstrated that individuals infected with pandemic 2009 (p2009) IAV experienced a boost in virus-neutralizing antibodies specific to the HA stalk [13]. This phenomenon has also been recently confirmed in a mouse model of sequential infection [14]. Importantly, other groups have observed naturally occurring HA stem antibodies in individuals who received a seasonal vaccine containing H1 and H3 viruses [15] or an H5N1 vaccine. Likewise, recent studies have shown that monoclonal antibodies and antibody-producing cells specific to the HA stem could be isolated from individuals who received the p2009 IAV vaccine [16, 17].

The HA segment of A/California/04/09 (Cal/09) virus descends from a separate lineage than that of previously circulating seasonal H1N1 strains. However, it is closely related to the HA segments of the A/New Jersey/1976 (NJ/76) virus and to the 1918 “Spanish Flu” [18, 19]. We therefore reasoned that individuals who received the NJ/76 vaccine or the Cal/09 vaccine may have also experienced a boost in cross-neutralizing antibodies specific to the HA stalk.

To investigate this possibility, we examined 2 cohorts of subjects for the presence of HA stalk antibodies. One cohort consisted of individuals who received the NJ/76 vaccine as well as the Cal/09 vaccine. The second cohort of age-matched controls received the Cal/09 vaccine only. We demonstrate that individuals who received the NJ/76 vaccine had elevated levels of anti-HA stalk antibodies prior to receiving the Cal/09 vaccine. Vaccination with Cal/09 boosted titers of anti-HA stalk antibodies only in subjects who had not been vaccinated with NJ/76. Importantly, receipt of the NJ/76 vaccine or the Cal/09 vaccine led to an enhanced neutralization response against a virus containing a homologous HA stalk and a heterosubtypic HA head. These findings confirm that anti-HA stalk antibodies were elicited by the NJ/76 and Cal/09 vaccines and enhance our understanding of the mechanisms through which these antibodies are generated naturally. This raises the exciting possibility that generation of vaccine constructs designed to specifically boost titers of HA stalk antibodies may lead to a universal influenza virus vaccine, capable of broad and long-lasting protection against diverse IAV strains.

1976 and 2009 H1N1 Influenza Virus Vaccines Boost Anti-Hemagglutinin Stalk Antibodies in Humans

Effect of Lactobacillus paracasei subsp. paracasei, L. casei 431 on immune response to influenza vaccination and upper respiratory tract infections in healthy adult volunteers: a randomized, double-blind, placebo-controlled, parallel-group study

Prevention of seasonal influenza epidemics and pandemics relies on widespread vaccination coverage to induce protective immunity. In addition to a good antigenic match with the circulating viruses, the effectiveness of individual strains represented in the trivalent vaccines depends on their immunogenicity. In this study, we evaluated the immunogenicity of H1N1, H3N2, and B seasonal influenza virus vaccine strains delivered individually with a novel dissolving microneedle patch and the stability of this formulation during storage at 25 °C. Our data demonstrate that all strains retained their antigenic activity after incorporation in the dissolving patches as measured by single radial diffusion (SRID) assay and immune responses to vaccination in BALB/c mice. After a single immunization, all three antigens delivered with microneedle patches induced superior neutralizing antibody titers compared to intramuscular immunization. Cutaneous antigen delivery was especially beneficial for the less immunogenic B strain. Mice immunized with dissolving microneedle patches encapsulating influenza A/Brisbane/59/07 (H1N1) vaccine were fully protected against lethal challenge by homologous mouse-adapted influenza virus. All vaccine components retained activity during storage at room temperature for at least 3 months as measured in vitro by SRID assay and in vivo by mouse immunization studies. Our data demonstrate that dissolving microneedle patches are a promising advance for influenza cutaneous vaccination due to improved immune responses using less immunogenic influenza antigens and enhanced stability.

/pdf/improved-immunogenicity-of-individual-influenza-vaccine-4wh1j7m0oc.pdf

Improved immunogenicity of individual influenza vaccine components delivered with a novel dissolving microneedle patch stable at room temperature.

Pandemic 2009 H1N1 influenza A virus (2009 H1N1) differs from H1N1 strains that circulated in the past 50 years, but resembles the A/New Jersey/1976 H1N1 strain used in the 1976 swine influenza vaccine. We investigated whether sera from persons immunized with the 1976 swine influenza or recent seasonal influenza vaccines, or both, neutralize 2009 H1N1. Using retroviral pseudovirions bearing hemagglutinins on their surface (HA-pseudotypes), we found that 77% of the sera collected in 1976 after immunization with the A/New Jersey/1976 H1N1 swine influenza vaccine neutralized 2009 H1N1. Forty five percent also neutralized A/New Caledonia/20/1999 H1N1, a strain used in seasonal influenza vaccines during the 2000/01-2006/07 seasons. Among adults aged 48-64 who received the swine influenza vaccine in 1976 and recent seasonal influenza vaccines during the 2004/05-2008/09 seasons, 83% had sera that neutralized 2009 H1N1. However, 68% of age-matched subjects who received the same seasonal influenza vaccines, but did not receive the 1976 swine influenza vaccine, also had sera that neutralized 2009 H1N1. Sera from both 1976 and contemporary cohorts frequently had cross-neutralizing antibodies to 2009 H1N1 and A/New Caledonia/20/1999 that mapped to hemagglutinin subunit 2 (HA2). A conservative mutation in HA2 corresponding to a residue in the A/Solomon Islands/3/2006 and A/Brisbane/59/2007 H1N1 strains that circulated in the 2006/07 and 2007/08 influenza seasons, respectively, abrogated this neutralization. These findings highlight a cross-neutralization determinant influenced by a point mutation in HA2 and suggest that HA2 may be evolving under direct or indirect immune pressure.

Cross-Neutralizing Antibodies to Pandemic 2009 H1N1 and Recent Seasonal H1N1 Influenza A Strains Influenced by a Mutation in Hemagglutinin Subunit 2

The campaign of 2009-2010 Northern Hemisphere seasonal vaccination was concurrent with the 2009 H1N1 pandemic. Using a hemagglutination inhibition (HAI) assay, we evaluated the immunogenicity and cross-reactivity of 2009-2010 inactivated trivalent influenza vaccine (TIV) in US adult and elderly populations. Vaccination of TIV resulted in a robust boost on the antibody response of all subjects to seasonal A/Brisbane/59/2007 (H1N1) and A/Uruguay/716/2007 (H3N2) with over 70% of recipients reaching a seroprotective titer of 40. B/Brisbane/60/2008 was the least immunogenic among the three seasonal vaccine strains with <30% of TIV recipients reaching a seroprotective titer of 40. TIV vaccination also induced a moderate boost on the pandemic specific antibody responses. Twenty-four percent of adults and 36% of elderly reached a seroprotective HAI titer of 40 or more against pandemic A/South Carolina/18/2009 (H1N1) after receiving TIV compared to 4% and 7% at the beginning of vaccination, respectively. In addition, 22% of adults and 34% of elderly showed an increase of 4-fold or more in A/South Carolina/18/2009 specific HAI titers after TIV vaccination. The pandemic specific cross-reactive antibodies strongly correlated with the post-vaccination HAI titers against the seasonal H3N2 vaccine strain in all subjects.

/pdf/immunogenicity-and-cross-reactivity-of-2009-2010-inactivated-7crbmpf6u4.pdf

Immunogenicity and Cross-Reactivity of 2009–2010 Inactivated Seasonal Influenza Vaccine in US Adults and Elderly

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Cross-Neutralizing Antibodies to Pandemic 2009 H1N1 and Recent Seasonal H1N1 Influenza A Strains Influenced by a Mutation in Hemagglutinin Subunit 2

Immunogenicity and Cross-Reactivity of 2009–2010 Inactivated Seasonal Influenza Vaccine in US Adults and Elderly