Florian Krammer

• DI Dr.
• Icahn School of Medicine at Mount Sinai

Public antibodies that recognize conserved epitopes are critical for vaccine development, and identifying somatic hypermutations (SHMs) that enhance antigen affinity in these public responses is key to guiding vaccine design for better protection. We propose that affinity-enhancing SHMs are selectively enriched in public antibody clonotypes, surpas...

The evolution of the antibody response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is impacted by the nature and number of antigenic exposures. First-generation coronavirus disease 2019 (COVID-19) vaccines encoded an ancestral spike protein. Updated bivalent vaccines and breakthrough infections have shaped the intricate dive...

Background Orthohantaviruses (hantaviruses) are emerging rodent-borne pathogens that can cause severe human disease. They are present on multiple continents and are responsible for thousands of human cases per year, predominantly in China. Despite this, no vaccines or licensed therapeutics are available, and the immunological response to infection...

Influenza virus neuraminidase (NA) has emerged as a promising vaccine candidate due to its relatively stable antigenic structure and the ability of NA-specific antibodies to provide cross-protection within influenza virus subtypes. Since the influenza virus causes respiratory infections in humans, developing mucosal vaccines to protect the entry si...

The highly pathogenic avian influenza H5N1 virus clade 2.3.4.4b has been spreading globally since 2022, causing mortality and morbidity in domestic and wild birds and mammals, including infection in humans, raising concerns about its pandemic potential. We aimed to generate a panel of anti-hemagglutinin (HA) human monoclonal antibodies (mAbs) again...

Following SARS-CoV-2 infection, ~10-35% of COVID-19 patients experience long COVID (LC), in which often debilitating symptoms persist for at least three months. Elucidating the biologic underpinnings of LC could identify therapeutic opportunities. We utilized machine learning methods on biologic analytes and patient reported outcome surveys provide...

The post-acute sequelae of SARS-CoV-2 (PASC), also known as long COVID, remain a significant health issue that is incompletely understood. Predicting which acutely infected individuals will go on to develop long COVID is challenging due to the lack of established biomarkers, clear disease mechanisms, or well-defined sub-phenotypes. Machine learning...

Chimeric hemagglutinins (cHA) appear to be promising for the design and development of universal influenza vaccines. Influenza A group 1 cHAs, cH5/1, cH8/1, and cH11/1, comprising an H1 stem attached to either an H5, H8, or H11 globular head, have been used sequentially as vaccine immunogens in human clinical trials and induced high levels of broad...

H1N1 influenza viruses are responsible for both seasonal and pandemic influenza. The continual antigenic shift and drift of these viruses highlight the urgent need for a universal influenza vaccine to elicit broadly neutralizing antibodies (bnAbs). Identification and characterization of bnAbs elicited in natural infection and immunization to influe...

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global health challenge, causing severe morbidity and mortality, particularly in vulnerable groups such as the elderly, immunocompromised individuals, and those with comorbidities. In low- and middle-income countries (LMICs), vaccine access is hindered by high costs and inequita...

Predicting individual vaccine responses remains a significant challenge due to the complexity and variability of immune processes. To address this gap, we developed immunaut , an open-source, data-driven framework implemented as an R package specifically designed for all systems vaccinologists seeking to analyze and predict immunological outcomes a...

Orthohantaviruses are emerging zoonotic viruses that can infect humans via the respiratory tract. There is an unmet need for an in vivo model to study infection of different orthohantaviruses in physiologically relevant tissue and to assess the efficacy of novel pan-orthohantavirus countermeasures. Here, we describe the use of a human lung xenograf...

Background The emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants challenges the treatment of immunocompromised patients against coronavirus disease 2019 (COVID-19). High-titer COVID-19 convalescent plasma (CCP) remains one of the few available therapeutics for these patients. We have revisited the selection of C...

Frequent recent spillovers of subtype H5N1 clade 2.3.4.4b highly pathogenic avian influenza (HPAI) virus into poultry and mammals, especially dairy cattle, including several human cases, increased concerns over a possible future pandemic. Here, we performed an analysis of epitope data curated in the Immune Epitope Database (IEDB). We found that the...

Antibodies are crucial therapeutics, comprising a significant portion of approved drugs due to their safety and clinical efficacy. Traditional antibody discovery methods are labor-intensive, limiting scalability and high-throughput analysis. Here, we improved upon our streamlined approach combining structural analysis and bioinformatics to infer he...

Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and lower-middle-income countries is needed. NDV-HXP-S is an inactivated egg-based recombinant Newcastle disease virus vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A public sector manufacturer in Vietnam assessed th...

Hospitalized COVID-19 patients exhibit diverse immune responses during acute infection, which are associated with a wide range of clinical outcomes. However, understanding these immune heterogeneities and their links to various clinical complications, especially long COVID, remains a challenge. In this study, we performed unsupervised subtyping of...

We have developed a new universal influenza B vaccination strategy based on inactivated influenza B viruses displaying mosaic hemagglutinins (mHAs). Recombinant mHA viruses were constructed by replacing the four major antigenic sites of influenza B virus HAs, with those from exotic avian influenza A virus HAs. Sequential vaccination of naïve mice w...

Background: Highly transmissible SARS-CoV-2 variants of concern such as Omicron XBB1.5 are of concern for patients that are immunocompromised. Patients with Multiple Myeloma (MM) remain particularly vulnerable due to therapies that deplete the machinery necessary for efficient humoral and cellular responses. MM patients continue to have an increase...

Neutralizing antibodies correlate with protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent studies, however, show that binding antibody titers, in the absence of robust neutralizing activity, also correlate with protection against disease progression. Non-neutralizing antibodies cannot directly protect against in...

Background This report summarizes the discussions and conclusions from the “Correlates of Protection for Next Generation Influenza Vaccines: Lessons Learned from the COVID‐19 Pandemic” meeting, which took place in Seattle, USA, from March 1, 2023, to March 3, 2023. Conclusions Discussions around influenza virus correlates of protection and their u...

The concept of mRNA-based vaccines emerged more than three decades ago. Groundbreaking discoveries and technological advancements over the past 20 years have resolved the major roadblocks that initially delayed application of this new vaccine modality. The rapid development of nucleoside-modified COVID-19 mRNA vaccines demonstrated that this immuni...

In 2021, an ultra-rapid rollout vaccination campaign in the Schwaz district, Tyrol, Austria, delivered the COVID-19 vaccine BNT162b2 to 66.9% of eligible residents (dose 1: March 11–16, dose 2: April 8–13). Alongside the campaign, we recruited 11,955 residents into the prospective study REDUCE, of whom 3,859 participated in a booster vaccination in...

Influenza viruses continually evolve new antigenic variants, through mutations in epitopes of their major surface proteins, hemagglutinin (HA) and neuraminidase (NA). Antigenic drift potentiates the reinfection of previously infected individuals, but the contribution of this process to variability in annual epidemics is not well understood. Here, w...

Invariant natural killer T (iNKT) cells are glycolipid-reactive T cells with potent immunoregulatory properties. iNKT cells activated with the marine-sponge-derived glycolipid, α-galactosylceramide (αGC), provide a universal source of T-cell help that has shown considerable promise for a wide array of therapeutic applications. This includes harness...

Influenza viruses pose a threat to public health as evidenced by severe morbidity and mortality in humans on a yearly basis. Given the constant changes in the viral glycoproteins owing to antigenic drift, seasonal influenza vaccines need to be updated periodically and effectiveness often drops due to mismatches between vaccine and circulating strai...

Many different platforms have been used to develop highly protective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in humans. However, protection has eroded over time due to the emergence of antigenically diverse viral variants, especially the Omicron subvariants. One successful platform for the generation of SARS-Co...

Live attenuated influenza vaccines (LAIV) typically induce a poor hemagglutination inhibition (HI) response, which is the standard correlate of protection for inactivated influenza vaccines. The significance of the HI response is complicated because the LAIV vaccine primarily induces the local mucosal immune system, while the HI assay measures the...

Sero-monitoring provides context to the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and changes in population immunity following vaccine introduction. Here, we describe results of a cross-sectional hospital-based study of anti-spike seroprevalence in New York City (NYC) from February 2020 to July 2022, an...

Background In order to prevent the emergence and spread of future variants of concern of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), developing vaccines capable of stopping transmission is crucial. The SARS-CoV-2 vaccine NDV-HXP-S can be administered live intranasally (IN) and thus induce protective immunity in the upper respirato...

Germinal centers (GC) are microanatomical lymphoid structures where affinity-matured memory B cells and long-lived bone marrow plasma cells are primarily generated. It is unclear how the maturation of B cells within the GC impacts the breadth and durability of B cell responses to influenza vaccination in humans. We used fine needle aspiration of dr...

In patients with lung cancer (LC), understanding factors that impact the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) anti-spike antibody (SAb) titers over time is critical, but challenging, due to evolving treatments, infections, vaccinations, and health status. The objective was to develop a time-dependent regression m...

Monoclonal antibodies (mAbs) are an attractive therapeutic platform for the prevention and treatment of influenza virus infection. There are two major glycoproteins on the influenza virion surface: hemagglutinin (HA), which is responsible for viral attachment and entry, and neuraminidase (NA), which mediates viral egress by enzymatically cleaving s...

Immune responses against neuraminidase (NA) are of great interest for developing more robust influenza vaccines, but the role of anti-NA antibodies on influenza infectivity has not been established. We conducted household transmission studies in Managua, Nicaragua to examine the impact of anti-NA antibodies on influenza A/H3N2 susceptibility and in...

Vaccination against influenza virus can reduce the risk of influenza by 40% to 60%, they rely on the production of neutralizing antibodies specific to influenza hemagglutinin (HA) ignoring the neuraminidase (NA) as an important surface target. Vaccination with standardized NA concentration may offer broader and longer-lasting protection against inf...

Introduction Several effective vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and implemented in the population. However, the current production capacity falls short of meeting global demand. Therefore, it is crucial to further develop novel vaccine platforms that can bridge the distribution gap. AVX/C...

Background: This report summarizes the discussions and conclusions from the “Correlates of Protection for Next Generation Influenza Vaccines: Lessons Learned from the COVID-19 Pandemic” meeting which took place in Seattle, USA, from March 1, 2023, to March 3, 2023. Conclusions: Discussions around influenza virus correlates of protection and their u...

Background The development of a universal influenza virus vaccine, to protect against both seasonal and pandemic influenza A viruses, is a long-standing public health goal. The conserved stalk domain of haemagglutinin (HA) is a promising vaccine target. However, the stalk is immunosubdominant. As such, innovative approaches are required to elicit r...

The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires ongoing monitoring to judge the ability of newly arising variants to escape the immune response. A surveillance system necessitates an understanding of differences in neutralization titers measured in different assays and using human and animal serum samples. We...

Highly pathogenic avian influenza viruses of the H5N1 clade 2.3.4.4b were detected in North America in the winter of 2021/2022. These viruses have spread across the Americas, causing morbidity and mortality in both wild and domestic birds as well as some mammalian species, including cattle. Many surveillance programs for wildlife as well as commerc...

Background Several influenza vaccine candidates aim to elicit antibodies against the conserved hemagglutinin stalk domain. Understanding the protective mechanism of these antibodies, which mediate broad neutralization and Fc-mediated functions, following seasonal vaccination is critical. Methods Plasma samples were obtained from a subset of pregna...

Background Influenza virus remains a threat to human health, but gaps remain in our knowledge of the humoral correlates of protection against influenza virus A/H3N2, limiting our ability to generate effective, broadly protective vaccines. The role of antibodies against the hemagglutinin (HA) stalk, a highly conserved but immunologically sub-dominan...

BACKGROUND Patients hospitalized for COVID-19 exhibit diverse clinical outcomes, with outcomes for some individuals diverging over time even though their initial disease severity appears similar to that of other patients. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coord...

The goal of this study is to characterize how proteomic signatures differ following COVID-19 vaccination in individuals naïve to SARS-CoV-2 infection (CoV-N) and those with a prior history of infection (CoV-P) to better understand the influence of pre-infection on host responses to vaccination. A subset of individuals (n = 63) enrolled in our IRB-a...

Background: Gaps remain in our knowledge of the humoral correlates of protection against influenza A/H3N2, including the role of antibodies against the hemagglutinin stalk, a highly conserved but immunologically sub-dominant region. Methods: Two household studies were conducted in Managua, Nicaragua. Household contacts were tested for influenza usi...

The SARS-CoV-2 spike (S) protein is an essential target for neutralizing antibodies, accumulating mutations, and generating variants of concern (VOC). The Omicron variant is a VOC that continues to evolve into antibody-resistant subvariants, such as XBB1.5. This led to the approval of an updated mRNA vaccine and a protein-based vaccine to target th...

Influenza A viruses (IAVs) of subtype H9N2 have reached an endemic stage in poultry farms in the Middle East and Asia. As a result, human infections with avian H9N2 viruses have been increasingly reported. In 2017, an H9N2 virus was isolated for the first time from Egyptian fruit bats (Rousettus aegyptiacus). Phylogenetic analyses revealed that bat...

Age is a major risk factor for severe coronavirus disease 2019 (COVID-19), yet the mechanisms behind this relationship have remained incompletely understood. To address this, we evaluated the impact of aging on host immune response in the blood and the upper airway, as well as the nasal microbiome in a prospective, multicenter cohort of 1031 vaccin...

Highly pathogenic avian influenza viruses of the H5N1 clade 2.3.4.4b arrived in North America in the winter of 2021/2022. These viruses have spread across the Americas causing morbidity and mortality in both wild and domestic birds as well as some mammalian species, including cattle. Many surveillance programs in wildlife as well as commercial poul...

Post vaccine immunity following COVID-19 mRNA vaccination may be driven by extrinsic, or controllable and intrinsic, or inherent health factors. Thus, we investigated the effects of extrinsic and intrinsic on the peak antibody response following COVID-19 primary vaccination and on the trajectory of peak antibody magnitude and durability over time....

The primary mode of transmission for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is infection of the respiratory tract through droplets and/or aerosols. Therefore, immune responses at respiratory mucosal surfaces play a significant role in the prevention of infection. Greater emphasis is now being placed on mucosal immunity induced...

Subvariants of the Omicron lineage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) efficiently escape neutralizing antibody responses induced by both vaccination and infection with antigenically distinct variants. Here, we describe the potency and breadth of neutralizing and binding antibody responses against a large panel of varian...

Orthohantaviruses are emerging zoonotic viruses that can infect humans via the respiratory tract. There is a clear unmet need for an in vivo model to study orthohantavirus infection in physiologically relevant tissue and to determine the broad reactivity of novel orthohantavirus countermeasures. Here, we describe the use of a human lung xenograft m...

Several effective vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and implemented in the population. However, the current production capacity falls short of meeting global demand. Therefore, it is crucial to further develop novel vaccine platforms that can bridge the distribution gap. AVX/COVID-12 is a...

Neutralizing antibodies correlate with protection against SARS-CoV-2. Recent studies, however, show that binding antibody titers, in the absence of robust neutralizing activity, also correlate with protection from disease progression. Non-neutralizing antibodies cannot directly protect from infection but may recruit effector cells thus contribute t...

Associations between antenatal SARS-CoV-2 infection and pregnancy outcomes have been conflicting and the role of the immune system is currently unclear. This prospective cohort study investigated the interaction of antenatal SARS-CoV-2 infection, changes in cytokine and HS-CRP levels, birthweight and gestational age at birth. 2352 pregnant particip...

Background: The urgent need for safe, effective, and economical coronavirus disease 2019 (COVID-19) vaccines, especially for booster campaigns targeting vulnerable populations, prompted the development of the AVX/COVID-12 vaccine candidate. AVX/COVD-12 is based in a Newcastle disease virus La Sota (NDV-LaSota) recombinant viral vector. This vaccine...

Background: The global inequity in coronavirus disease 2019 (COVID-19) vaccine distribution, primarily affecting low- and middle-income countries (LMICs), highlights the urgent need for innovative and cost-effective vaccine technologies to address availability disparities. This is crucial for achieving and sustaining widespread immunity and protect...

Age is a major risk factor for severe coronavirus disease-2019 (COVID-19), yet the mechanisms responsible for this relationship have remained incompletely understood. To address this, we evaluated the impact of aging on host and viral dynamics in a prospective, multicenter cohort of 1,031 patients hospitalized for COVID-19, ranging from 18 to 96 ye...

The baculovirus/insect cell expression system is a very useful tool for reagent and antigen generation in vaccinology, virology, and immunology. It allows for the production of recombinant glycoproteins, which are used as antigens in vaccination studies and as reagents in immunological assays. Here, we describe the process of recombinant glycoprote...

The glycosylation of IgG plays a critical role during human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, activating immune cells and inducing cytokine production. However, the role of IgM N-glycosylation has not been studied during human acute viral infection. The analysis of IgM N-glycosylation from healthy controls and...

Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge. Modeling identified 4 PRO clusters based on reported deficits (minimal, physical, mental/cognitive, and multid...

The Orthocoronavirinae subfamily is large comprising four highly divergent genera. Four seasonal coronaviruses were circulating in humans prior to the coronavirus disease 2019 pandemic. Infection with these viruses induced antibody responses that are relatively narrow with little cross-reactivity to spike proteins of other coronaviruses. Here, we r...

Sero-monitoring provides context to the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and changes in population immunity following vaccine introduction. Here, we describe results of a cross-sectional hospital-based study of anti-spike seroprevalence in New York City (NYC) from February 2020 to July 2022, an...

Coronavirus disease 2019 (COVID-19) vaccines have saved millions of lives. However, variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged causing large numbers of breakthrough infections. These developments necessitated the rollout of COVID-19 vaccine booster doses. It has been reported that mucosal antibody levels i...

Background Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and lower-middle-income countries is needed. NDV-HXP-S is an inactivated egg-based recombinant Newcastle disease virus vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A public sector manufacturer in Vietnam...

Background: In response to the ever-evolving challenges posed by the antigenically diverse Omicron variants, the deployment of bivalent mRNA booster vaccines encompassing both the ancestral (WA1) and Omicron BA.5 spike components was initiated in fall of 2022. The real-world impact of these bivalent vaccines is largely unknown in patients with Mult...

Whereas COVID-19 mRNA vaccines have shown remarkable efficacy in the prevention of severe disease and mortality in healthy individuals, the effectiveness in cancer patients has been more variable. Patients with multiple myeloma (MM) are at a high risk for severe infection due to disease- or treatment-related immune suppression. Our prior work demon...

Vaccines that protect against any H1N1 influenza A virus strain would be advantageous for use in pigs and humans. Here, we try to induce a pan-H1N1 antibody response in pigs by sequential vaccination with antigenically divergent H1N1 strains. Adjuvanted whole inactivated vaccines are given intramuscularly in various two- and three-dose regimens. Th...

Objective The effect of stress on vaccine-induced humoral immunity and therapeutic interventions to mitigate pandemic-related stress remain under-explored. Methods Participants in a longitudinal cohort study (n = 189) completed a validated measure, 7-instrument Generalized Anxiety Disorder (GAD-7), and 10-instrument stress measure (SM-10) to asses...

Coronavirus disease 2019 (COVID-19) poses significant risks for solid organ transplant (SOT) recipients, who have atypical but poorly characterized immune responses to SARS-CoV-2 infection. We sought to understand the host immunologic and microbial features of COVID-19 in SOT recipients by leveraging a prospective multicenter cohort of 1164 hospita...

Hospitalized COVID-19 patients exhibit diverse clinical outcomes, with some individuals diverging over time even though their initial disease severity appears similar. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity. In this study,...

Improved broad-spectrum influenza virus vaccines are desperately needed to provide protection against both drifted seasonal and emerging pandemic influenza A viruses (IAVs). Antibody-based protection from influenza A virus-induced morbidity and mortality is traditionally associated with neutralizing antibodies. As such, vaccine efforts have solely...