AS03 adjuvant enhances the magnitude, persistence, and clonal breadth of memory B cell responses to a plant-based COVID-19 vaccine in humans.

Vaccine adjuvants increase the breadth of serum antibody responses, but whether this is due to the generation of antigen-specific B cell clones with distinct specificities or the maturation of memory B cell clones that produce broadly cross-reactive antibodies is unknown. Here, we longitudinally analyzed immune responses in healthy adults after two-dose vaccination with either a virus-like particle COVID-19 vaccine (CoVLP), CoVLP adjuvanted with AS03 (CoVLP+AS03), or a messenger RNA vaccination (mRNA-1273). CoVLP+AS03 enhanced the magnitude and durability of circulating antibodies and antigen-specific CD4+ T cell and memory B cell responses. Antigen-specific CD4+ T cells in the CoVLP+AS03 group at day 42 correlated with antigen-specific memory B cells at 6 months. CoVLP+AS03 induced memory B cell responses, which accumulated somatic hypermutations over 6 months, resulting in enhanced neutralization breadth of monoclonal antibodies. Furthermore, the fraction of broadly neutralizing antibodies encoded by memory B cells increased between day 42 and 6 months. These results indicate that AS03 enhances the antigenic breadth of B cell memory at the clonal level and induces progressive maturation of the B cell response.

Features of acute COVID-19 associated with post-acute sequelae of SARS-CoV-2 phenotypes: results from the IMPACC study.

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 multidomain), supporting heterogenous clinical presentations in PASC, with sub-phenotypes associated with female sex and distinctive comorbidities. During the acute phase of disease, a higher respiratory SARS-CoV-2 viral burden and lower Receptor Binding Domain and Spike antibody titers were associated with both the physical predominant and the multidomain deficit clusters. A lower frequency of circulating B lymphocytes by mass cytometry (CyTOF) was observed in the multidomain deficit cluster. Circulating fibroblast growth factor 21 (FGF21) was significantly elevated in the mental/cognitive predominant and the multidomain clusters. Future efforts to link PASC to acute anti-viral host responses may help to better target treatment and prevention of PASC.

Comparison of bivalent and monovalent SARS-CoV-2 variant vaccines: the phase 2 randomized open-label COVAIL trial.

Vaccine protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection wanes over time, requiring updated boosters. In a phase 2, open-label, randomized clinical trial with sequentially enrolled stages at 22 US sites, we assessed safety and immunogenicity of a second boost with monovalent or bivalent variant vaccines from mRNA and protein-based platforms targeting wild-type, Beta, Delta and Omicron BA.1 spike antigens. The primary outcome was pseudovirus neutralization titers at 50% inhibitory dilution (ID50 titers) with 95% confidence intervals against different SARS-CoV-2 strains. The secondary outcome assessed safety by solicited local and systemic adverse events (AEs), unsolicited AEs, serious AEs and AEs of special interest. Boosting with prototype/wild-type vaccines produced numerically lower ID50 titers than any variant-containing vaccine against all variants. Conversely, boosting with a variant vaccine excluding prototype was not associated with decreased neutralization against D614G. Omicron BA.1 or Beta monovalent vaccines were nearly equivalent to Omicron BA.1 + prototype or Beta + prototype bivalent vaccines for neutralization of Beta, Omicron BA.1 and Omicron BA.4/5, although they were lower for contemporaneous Omicron subvariants. Safety was similar across arms and stages and comparable to previous reports. Our study shows that updated vaccines targeting Beta or Omicron BA.1 provide broadly crossprotective neutralizing antibody responses against diverse SARS-CoV-2 variants without sacrificing immunity to the ancestral strain. ClinicalTrials.gov registration: NCT05289037 .

Efficacy and Durability of Immune Response after Receipt of HPV Vaccines in People Living with HIV.

People living with HIV (PLH) experience higher rates of HPV infection as well as an increased risk of HPV-related disease, including malignancies. Although they are considered a high-priority group for HPV vaccination, there are limited data regarding the long-term immunogenicity and efficacy of HPV vaccines in this population. Seroconversion rates and geometric mean titers elicited by vaccination are lower in PLH compared to immunocompetent participants, especially in individuals with CD4 counts below 200 cells/mm3 and a detectable viral load. The significance of these differences is still unclear, as a correlate of protection has not been identified. Few studies have focused on demonstrating vaccine efficacy in PLH, with variable results depending on the age at vaccination and baseline seropositivity. Although waning humoral immunity for HPV seems to be more rapid in this population, there is evidence that suggests that seropositivity lasts at least 2-4 years following vaccination. Further research is needed to determine the differences between vaccine formulations and the impact of administrating additional doses on durability of immune protection.

Bivalent and Monovalent SARS-CoV-2 Variant Vaccine Boosters Improve coverage of the known Antigenic Landscape: Results of the COVID-19 Variant Immunologic Landscape (COVAIL) Trial.

Vaccine protection against COVID-19 wanes over time and has been impacted by the emergence of new variants with increasing escape of neutralization. The COVID-19 Variant Immunologic Landscape (COVAIL) randomized clinical trial (clinicaltrials.gov NCT05289037) compares the breadth, magnitude and durability of antibody responses induced by a second COVID-19 vaccine boost with mRNA (Moderna mRNA-1273 and Pfizer-BioNTech BNT162b2), or adjuvanted recombinant protein (Sanofi CoV2 preS DTM-AS03) monovalent or bivalent vaccine candidates targeting ancestral and variant SARS-CoV-2 spike antigens (Beta, Delta and Omicron BA.1). We found that boosting with a variant strain is not associated with loss in neutralization against the ancestral strain. However, while variant vaccines compared to the prototype/wildtype vaccines demonstrated higher neutralizing activity against Omicron BA.1 and BA.4/5 subvariants for up to 3 months after vaccination, neutralizing activity was lower for more recent Omicron subvariants. Our study, incorporating both antigenic distances and serologic landscapes, can provide a framework for objectively guiding decisions for future vaccine updates.

Heterologous versus homologous boosting elicits qualitatively distinct, BA.5-cross-reactive T cells in transplant recipients.

BackgroundThe SARS-CoV-2 Omicron BA.5 subvariant escapes vaccination-induced neutralizing antibodies because of mutations in the spike (S) protein. Solid organ transplant recipients (SOTRs) develop high COVID-19 morbidity and poor Omicron variant recognition after COVID-19 vaccination. T cell responses may provide a second line of defense. Therefore, understanding which vaccine regimens induce robust, conserved T cell responses is critical.MethodsWe evaluated anti-S IgG titers, subvariant pseudo-neutralization, and S-specific CD4+ and CD8+ T cell responses from SOTRs in a national, prospective, observational trial (n = 75). Participants were selected if they received 3 doses of mRNA (homologous boosting) or 2 doses of mRNA followed by Ad26.COV2.S (heterologous boosting).ResultsHomologous boosting with 3 mRNA doses induced the highest anti-S IgG titers. However, antibodies induced by both vaccine regimens demonstrated lower pseudo-neutralization against BA.5 compared with the ancestral strain. In contrast, vaccine-induced S-specific T cells maintained cross-reactivity against BA.5 compared with ancestral recognition. Homologous boosting induced higher frequencies of activated polyfunctional CD4+ T cell responses, with polyfunctional IL-21+ peripheral T follicular helper cells increased in mRNA-1273 compared with BNT162b2. IL-21+ cells correlated with antibody titers. Heterologous boosting with Ad26.COV2.S did not increase CD8+ responses compared to homologous boosting.ConclusionBoosting with the ancestral strain can induce cross-reactive T cell responses against emerging variants in SOTRs, but alternative vaccine strategies are required to induce robust CD8+ T cell responses.FundingBen-Dov Family; NIH National Institute of Allergy and Infectious Diseases (NIAID) K24AI144954, NIAID K08AI156021, NIAID K23AI157893, NIAID U01AI138897, National Institute of Diabetes and Digestive and Kidney Diseases T32DK007713, and National Cancer Institute 1U54CA260492; Johns Hopkins Vice Dean of Research Support for COVID-19 Research in Immunopathogenesis; and Emory COVID-19 research repository.

Persistent SARS-CoV-2-specific immune defects in kidney transplant recipients following third mRNA vaccine dose.

Kidney transplant recipients (KTRs) show poorer response to SARS-CoV-2 mRNA vaccination, yet response patterns and mechanistic drivers following third doses are ill-defined. We administered third monovalent mRNA vaccines to n = 81 KTRs with negative or low-titer anti-receptor binding domain (RBD) antibody (n = 39 anti-RBDNEG; n = 42 anti-RBDLO), compared with healthy controls (HCs, n = 19), measuring anti-RBD, Omicron neutralization, spike-specific CD8+%, and SARS-CoV-2-reactive T cell receptor (TCR) repertoires. By day 30, 44% anti-RBDNEG remained seronegative; 5% KTRs developed BA.5 neutralization (vs 68% HCs, P < .001). Day 30 spike-specific CD8+% was negative in 91% KTRs (vs 20% HCs; P = .07), without correlation to anti-RBD (rs = 0.17). Day 30 SARS-CoV-2-reactive TCR repertoires were detected in 52% KTRs vs 74% HCs (P = .11). Spike-specific CD4+ TCR expansion was similar between KTRs and HCs, yet KTR CD8+ TCR depth was 7.6-fold lower (P = .001). Global negative response was seen in 7% KTRs, associated with high-dose MMF (P = .037); 44% showed global positive response. Of the KTRs, 16% experienced breakthrough infections, with 2 hospitalizations; prebreakthrough variant neutralization was poor. Absent neutralizing and CD8+ responses in KTRs indicate vulnerability to COVID-19 despite 3-dose mRNA vaccination. Lack of neutralization despite CD4+ expansion suggests B cell dysfunction and/or ineffective T cell help. Development of more effective KTR vaccine strategies is critical. (NCT04969263).

Durability of immune responses to mRNA booster vaccination against COVID-19.

BackgroundMaintaining durable immunity following vaccination represents a major challenge, but whether mRNA booster vaccination improves durability is unknown.MethodsWe measured antibody responses in 55 healthy adults, who received a booster dose of the Pfizer-BioNTech or Moderna vaccine against SARS-CoV-2 and calculated the half-life of the antibody titers. We also measured memory B and T cell responses in a subset of 28 participants. In 13 volunteers who received a second booster vaccine, we measured serum antibody titers and memory B and T cell responses.ResultsThe booster (third immunization) dose at 6 to 10 months increased the half-life of the serum-neutralizing antibody (nAb) titers to 76 days from 56 to 66 days after the primary 2-dose vaccination. A second booster dose (fourth immunization) a year after the primary vaccination further increased the half-life to 88 days. However, despite this modestly improved durability in nAb responses against the ancestral (WA.1) strain, there was a loss of neutralization capacity against the Omicron subvariants BA.2.75.2, BQ.1.1, and XBB.1.5 (48-, 71-, and 66-fold drop in titers, respectively, relative to the WA.1 strain). Although only 45% to 65% of participants demonstrated a detectable nAb titer against the newer variants after the booster (third dose), the response declined to below the detection limit in almost all individuals by 6 months. In contrast, booster vaccination induced antigen-specific memory B and T cells that persisted for at least 6 months.ConclusionThe durability of serum antibody responses improves only marginally following booster immunizations with the Pfizer-BioNTech or Moderna mRNA vaccines.

Durability of immune responses to the booster mRNA vaccination against COVID-19.

Waning immunity to vaccination represents a major challenge in vaccinology. Whether booster vaccination improves the durability of immune responses is unknown. Here we show, using a cohort of 55 adult vaccinees who received the BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine against SARS-CoV-2, that a booster (i.e., 3 rd immunization) dose at 6 - 10 months increased the half-life of serum neutralizing antibody (nAb) titers to 76 days from 56 - 66 days estimated after the primary two-dose vaccination series. A second booster dose (i.e., 4 th immunization) more than a year after the primary vaccination increased the half-life further to 88 days. However, despite this modestly improved durability in nAb responses against the Wuhan strain, there was a loss in neutralization capacity against Omicron subvariants, especially the recently emerged variants, BA.2.75.2 and BQ.1.1 (35 and 50-fold drop in titers respectively, relative to the ancestral (WA.1) strain. While only 55 â€" 65% of participants demonstrated a detectable nAb titer against the newer variants after the booster (3 rd dose), the response declined to below the detection limit in almost all individuals by 6 months. Notably, even against BA.1 and BA.5, the titers declined rapidly in a third of the vaccinees and were below the detection limit at 6 months. In contrast, booster vaccination induced antigen-specific memory B and T cells that persisted for at least 6 months. Collectively, our data show that the durability of immune responses improves following subsequent booster immunizations; however, the emergence of immune evasive variants reduces the effectiveness of booster doses in preventing infection.

mRNA bivalent booster enhances neutralization against BA.2.75.2 and BQ.1.1.

The emergence of the highly divergent SARS-CoV-2 Omicron variant has jeopardized the efficacy of vaccines based on the ancestral spike. The bivalent COVID-19 mRNA booster vaccine within the United States is comprised of the ancestral and the Omicron BA.5 spike. Since its approval and distribution, additional Omicron subvariants have been identified with key mutations within the spike protein receptor binding domain that are predicted to escape vaccine sera. Of particular concern is the R346T mutation which has arisen in multiple subvariants, including BA.2.75.2 and BQ.1.1. Using a live virus neutralization assay, we evaluated serum samples from individuals who had received either one or two monovalent boosters or the bivalent booster to determine neutralizing activity against wild-type (WA1/2020) virus and Omicron subvariants BA.1, BA.5, BA.2.75.2, and BQ.1.1. In the one monovalent booster cohort, relative to WA1/2020, we observed a reduction in neutralization titers of 9-15-fold against BA.1 and BA.5 and 28-39-fold against BA.2.75.2 and BQ.1.1. In the BA.5-containing bivalent booster cohort, the neutralizing activity improved against all the Omicron subvariants. Relative to WA1/2020, we observed a reduction in neutralization titers of 3.7- and 4-fold against BA.1 and BA.5, respectively, and 11.5- and 21-fold against BA.2.75.2 and BQ.1.1, respectively. These data suggest that the bivalent mRNA booster vaccine broadens humoral immunity against the Omicron subvariants.

SARS-CoV-2 Variant Vaccine Boosters Trial: Preliminary Analyses.

Background: Protection from SARS-CoV-2 vaccines wanes over time and is compounded by emerging variants including Omicron subvariants. This study evaluated safety and immunogenicity of SARS-CoV-2 variant vaccines. Methods: This phase 2 open-label, randomized trial enrolled healthy adults previously vaccinated with a SARS-CoV-2 primary series and a single boost. Eligible participants were randomized to one of six Moderna COVID19 mRNA vaccine arms (50µg dose): Prototype (mRNA-1273), Omicron BA.1+Beta (1 or 2 doses), Omicron BA.1+Delta, Omicron BA.1 monovalent, and Omicron BA.1+Prototype. Neutralization antibody titers (ID 50 ) were assessed for D614G, Delta, Beta and Omicron BA.1 variants and Omicron BA.2.12.1 and BA.4/BA.5 subvariants 15 days after vaccination. Results: From March 30 to May 6, 2022, 597 participants were randomized and vaccinated. Median age was 53 years, and 20% had a prior SARS-CoV-2 infection. All vaccines were safe and well-tolerated. Day 15 geometric mean titers (GMT) against D614G were similar across arms and ages, and higher with prior infection. For uninfected participants, Day 15 Omicron BA.1 GMTs were similar across Omicron-containing vaccine arms (3724-4561) and higher than Prototype (1,997 [95%CI:1,482-2,692]). The Omicron BA.1 monovalent and Omicron BA.1+Prototype vaccines induced a geometric mean ratio (GMR) to Prototype for Omicron BA.1 of 2.03 (97.5%CI:1.37-3.00) and 1.56 (97.5%CI:1.06-2.31), respectively. A subset of samples from uninfected participants in four arms were also tested in a different laboratory at Day 15 for neutralizing antibody titers to D614G and Omicron subvariants BA.1, BA.2.12.2 and BA.4/BA.5. Omicron BA.4/BA.5 GMTs were approximately one third BA.1 GMTs (Prototype 517 [95%CI:324-826] vs. 1503 [95%CI:949-2381]; Omicron BA.1+Beta 628 [95%CI:367-1,074] vs. 2125 [95%CI:1139-3965]; Omicron BA.1+Delta 765 [95%CI:443-1,322] vs. 2242 [95%CI:1218-4128] and Omicron BA.1+Prototype 635 [95%CI:447-903] vs. 1972 [95%CI:1337-2907). Conclusions: Higher Omicron BA.1 titers were observed with Omicron-containing vaccines compared to Prototype vaccine and titers against Omicron BA.4/BA.5 were lower than against BA.1 for all candidate vaccines. Clinicaltrialsgov: NCT05289037.

Calcification of the ascending aorta, left heart valves and coronaries: associated diseases and a new classification.

Aim: The topography of vascular and valvular calcification could help accurately predict cardiovascular post-operative complications. The data on these calcifications remains scarce. Purpose: Identify the topographic distribution of the ascending aortic, left heart valves and coronary calcifications. Materials & methods: We extracted 26 variables from 557 patients, hospitalized between 2017 and 2020. The topography of calcification was evaluated by thoracic CT scans. Both multivariate logistic regression and classification and regression tree (CART) were used for statistical analysis. Results: Several comorbidities were associated with vascular or valvular calcification. This study proposes a CART tree for patients according to their age, sex, Euroscore and lipid profile. Conclusion: The proposed classification could represent an important clinical tool. More studies are warranted to better prune the current CART algorithm.

The deposition of calcium in the aorta is a common problem that may lead to an increased risk of adverse events during or after cardiovascular procedures. The ascending aorta (AAo) is a portion of the aorta that has not been widely evaluated for deposition of calcium. This study aims to better identify the areas of deposition of calcium in the AAo, the valves and the coronary arteries. Chest CT scans from 557 patients have been reviewed to identify the location of calcification of the aorta and correlate this calcification profile with the patients' clinical profile. This enabled us to group patients according to their similar clinical profiles and formulate a primary prediction of the calcification state of their AAo without referring to imaging, thus potentially resulting in a quicker and more efficient assessment of the benefit/risk ratio when planning cardiovascular procedures.

mRNA-1273 and BNT162b2 mRNA vaccines have reduced neutralizing activity against the SARS-CoV-2 omicron variant.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron variant emerged in November 2021 and consists of several mutations within the spike. We use serum from mRNA-vaccinated individuals to measure neutralization activity against omicron in a live-virus assay. At 2-4 weeks after a primary series of vaccinations, we observe a 30-fold reduction in neutralizing activity against omicron. Six months after the initial two-vaccine doses, sera from naive vaccinated subjects show no neutralizing activity against omicron. In contrast, COVID-19-recovered individuals 6 months after receiving the primary series of vaccinations show a 22-fold reduction, with the majority of the subjects retaining neutralizing antibody responses. In naive individuals following a booster shot (third dose), we observe a 14-fold reduction in neutralizing activity against omicron, and over 90% of subjects show neutralizing activity. These findings show that a third dose is required to provide robust neutralizing antibody responses against the omicron variant.

mRNA-1273 and BNT162b2 mRNA vaccines have reduced neutralizing activity against the SARS-CoV-2 Omicron variant.

The BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) vaccines generate potent neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the global emergence of SARS-CoV-2 variants with mutations in the spike protein, the principal antigenic target of these vaccines, has raised concerns over the neutralizing activity of vaccine-induced antibody responses. The Omicron variant, which emerged in November 2021, consists of over 30 mutations within the spike protein. Here, we used an authentic live virus neutralization assay to examine the neutralizing activity of the SARS-CoV-2 Omicron variant against mRNA vaccine-induced antibody responses. Following the 2nd dose, we observed a 30-fold reduction in neutralizing activity against the omicron variant. Through six months after the 2nd dose, none of the sera from naïve vaccinated subjects showed neutralizing activity against the Omicron variant. In contrast, recovered vaccinated individuals showed a 22-fold reduction with more than half of the subjects retaining neutralizing antibody responses. Following a booster shot (3rd dose), we observed a 14-fold reduction in neutralizing activity against the omicron variant and over 90% of boosted subjects showed neutralizing activity against the omicron variant. These findings show that a 3rd dose is required to provide robust neutralizing antibody responses against the Omicron variant.