Abstract
Background
Ebolaviruses Ebola (EBOV), Sudan (SUDV), and Bundibugyo (BDBV) cause severe human disease, which may be accompanied by hemorrhagic syndrome, with high case fatality rates. ...Monovalent vaccines do not offer cross-protection against these viruses whose endemic areas overlap. Therefore, development of a panebolavirus vaccine is a priority. As a vaccine vector, human parainfluenza virus type 3 (HPIV3) has the advantages of needle-free administration and induction of both systemic and local mucosal antibody responses in the respiratory tract.
Methods
To minimize the antivector immunity, genes encoding the HPIV3 envelope proteins F and HN were removed from the vaccine constructs, resulting in expression of only the ebolavirus envelope protein—glycoprotein. These second-generation vaccine constructs were used to develop a combination vaccine against EBOV, SUDV, and BDBV.
Results
A single intranasal vaccination of guinea pigs or ferrets with the trivalent combination vaccine elicited humoral responses to each of the targeted ebolaviruses, including binding and neutralizing antibodies, as well as Fc-mediated effector functions. This vaccine protected animals from death and disease caused by lethal challenges with EBOV, SUDV, or BDBV.
Conclusions
The combination vaccine elicited protection that was comparable to that induced by the monovalent vaccines, thus demonstrating the value of this combination trivalent vaccine.
A single intranasal vaccination of guinea pigs or ferrets with the trivalent combination vaccine based on second-generation human parainfluenza virus type 3 vectors protected animals from death and disease caused by lethal dose of Ebola, Sudan, or Bundibugyo virus.
Preexisting cross-reactive antibodies have been implicated in both protection and pathogenesis during subsequent infections with different dengue virus (DENV) serotypes (DENV1-4). Nonetheless, ...humoral immune correlates and mechanisms of protection have remained elusive. Using a systems serology approach to evaluate humoral responses, we profiled plasma collected before inapparent or symptomatic secondary DENV3 infection from our pediatric cohort in Nicaragua. Children protected from symptomatic infections had more anti-envelope (E) and anti-nonstructural protein 1 (NS1) total immunoglobulin G (IgG), IgG4, and greater Fc effector functions than those with symptoms. Fc effector functions were also associated with protection from hemorrhagic manifestations in the pre-symptomatic group. Furthermore, in vitro virological assays using these plasma samples revealed that protection mediated by antibody-dependent complement deposition was associated with both lysis of virions and DENV-infected cells. These data suggest that E- and NS1-specific Fc functions may serve as correlates of protection, which can be potentially applied toward the design and evaluation of dengue vaccines.
Human immunodeficiency virus (HIV)-exposed, uninfected (HEU) children have a higher risk of severe infection, but the causes are poorly understood. Emerging data point to altered antibody transfer in ...women with HIV (WHIV); however, specific perturbations and the influence of antiretroviral therapy (ART) and HIV viremia remain unclear.
We evaluated antigen-specific transplacental antibody transfer across 14 antigens in paired maternal and umbilical cord plasma from 352 Ugandan women; 176 were WHIV taking ART. We measured antigen-specific immunoglobulin G (IgG) sub-class (IgG1, 2, 3, 4) levels and antibody Fcγ receptor (FcγRn, 2a, 2b, 3a, 3b) binding profiles. We used partial least squares discrimi-nant analysis to define antigen-specific transplacental antibody transfer features.
Global antibody transfer patterns were similar by maternal HIV serostatus, pointing to effective placental function in WHIV. However, HEU umbilical cord antibody profiles were altered, driven by perturbed WHIV seroprofiles, with higher levels of herpesvirus antibodies (P < .01 for Epstein-Barr virus, herpes simplex virus) and lower levels of classic vaccine-induced antibodies (P < .01 for tetanus, polio, Haemophilus influenzae type b), suggesting that umbilical cord antibody profile differences arise from imbalanced WHIV immunity. Abnormal WHIV antibody profiles were associated with HIV viremia, lower CD4 count, and postconception ART initiation (P = .01).
Perturbed immune-dominance profiles in WHIV shift the balance of immunity delivered to neonates. Perturbed HIV-associated maternal antibody profiles are a key determinant of com-promised neonatal immunity. Maternal vaccination interventions may promote transfer of relevant, effective antibodies to protect HEU children against early-life infections.
Protective Ebola virus (EBOV) antibodies have neutralizing activity and induction of antibody constant domain (Fc)-mediated innate immune effector functions. Efforts to enhance Fc effector ...functionality often focus on maximizing antibody-dependent cellular cytotoxicity, yet distinct combinations of functions could be critical for antibody-mediated protection. As neutralizing antibodies have been cloned from EBOV disease survivors, we sought to identify survivor Fc effector profiles to help guide Fc optimization strategies. Survivors developed a range of functional antibody responses, and we therefore applied a rapid, high-throughput Fc engineering platform to define the most protective profiles. We generated a library of Fc variants with identical antigen-binding fragments (Fabs) from an EBOV neutralizing antibody. Fc variants with antibody-mediated complement deposition and moderate natural killer (NK) cell activity demonstrated complete protective activity in a stringent in vivo mouse model. Our findings highlight the importance of specific effector functions in antibody-mediated protection, and the experimental platform presents a generalizable resource for identifying correlates of immunity to guide therapeutic antibody design.
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•Ebola virus disease survivors develop diverse profiles of antibody responses•Fc engineering of monoclonal antibodies can replicate human functional profiles•A Fc variant panel was generated using an anti-Ebola virus neutralizing Fab domain•Fc variants with high complement yet moderate ADCC activity were protective in vivo
Gunn et al. profile Ebola virus disease survivors and apply a platform for engineering antibody Fc domains to define protective profiles. Fc variants with complement deposition yet moderate NK cell activity completely protected infected mice from disease. This experimental platform can be used for identifying correlates of immunity to other pathogens and to guide therapeutic antibody design.
Although emerging data during the SARS-CoV-2 pandemic have demonstrated robust messenger RNA vaccine–induced immunogenicity across populations, including pregnant and lactating individuals, the rapid ...waning of vaccine-induced immunity and the emergence of variants of concern motivated the use of messenger RNA vaccine booster doses. Whether all populations, including pregnant and lactating individuals, will mount a comparable response to a booster dose is not known.
This study aimed to profile the humoral immune response to a COVID-19 messenger RNA booster dose in a cohort of pregnant, lactating, and nonpregnant age-matched women.
This study characterized the antibody response against ancestral Spike and Omicron in a cohort of 31 pregnant, 12 lactating, and 20 nonpregnant age-matched controls who received a BNT162b2 or messenger RNA-1273 booster dose after primary COVID-19 vaccination. In addition, this study examined the vaccine-induced antibody profiles of 15 maternal-to-cord dyads at delivery.
Receiving a booster dose during pregnancy resulted in increased immunoglobulin G1 levels against Omicron Spike (postprimary vaccination vs postbooster dose; P=.03). Pregnant and lactating individuals exhibited equivalent Spike-specific total immunoglobulin G1, immunoglobulin M, and immunoglobulin A levels and neutralizing titers against Omicron compared with nonpregnant women. Subtle differences in Fc receptor binding and antibody subclass profiles were observed in the immune response to a booster dose in pregnant vs nonpregnant individuals. The analysis of maternal and cord antibody profiles at delivery demonstrated equivalent total Spike-specific immunoglobulin G1 in maternal and cord blood, yet higher Spike-specific FcγR3a-binding antibodies in the cord relative to maternal blood (P=.002), consistent with the preferential transfer of highly functional immunoglobulin. Spike-specific immunoglobulin G1 levels in the cord were positively correlated with the time elapsed since receiving the booster dose (Spearman R, .574; P=.035).
Study data suggested that receiving a booster dose during pregnancy induces a robust Spike-specific humoral immune response, including against Omicron. If boosting occurs in the third trimester of pregnancy, higher Spike-specific cord immunoglobulin G1 levels are achieved with greater time elapsed between receiving the booster and delivery. Receiving a booster dose has the potential to augment maternal and neonatal immunity.
Mpox virus (MPXV) caused a global outbreak in 2022. Although smallpox vaccines were rapidly deployed to curb spread and disease among those at highest risk, breakthrough disease was noted after ...complete immunization. Given the threat of additional zoonotic events and the virus's evolving ability to drive human-to-human transmission, there is an urgent need for an MPXV-specific vaccine that confers protection against evolving MPXV strains and related orthopoxviruses. Here, we demonstrate that an mRNA-lipid nanoparticle vaccine encoding a set of four highly conserved MPXV surface proteins involved in virus attachment, entry, and transmission can induce MPXV-specific immunity and heterologous protection against a lethal vaccinia virus (VACV) challenge. Compared with modified vaccinia virus Ankara (MVA), which forms the basis for the current MPXV vaccine, immunization with an mRNA-based MPXV vaccine generated superior neutralizing activity against MPXV and VACV and more efficiently inhibited spread between cells. We also observed greater Fc effector T
1-biased humoral immunity to the four MPXV antigens encoded by the vaccine, as well as to the four VACV homologs. Single MPXV antigen-encoding mRNA vaccines provided partial protection against VACV challenge, whereas multivalent vaccines combining mRNAs encoding two, three, or four MPXV antigens protected against disease-related weight loss and death equal or superior to MVA vaccination. These data demonstrate that an mRNA-based MPXV vaccine confers robust protection against VACV.
Abstract
Individuals on immunosuppressive (IS) therapy have increased mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and delayed viral clearance may lead to ...new viral variants. IS therapy reduces antibody responses following coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccination; however, a comprehensive assessment of vaccine immunogenicity is lacking. Here we show that IS therapy reduced neutralizing, binding, and nonneutralizing antibody functions in addition to CD4 and CD8 T-cell interferon-γ responses following COVID-19 mRNA vaccination compared to immunocompetent individuals. Moreover, IS therapy reduced cross-reactivity against SARS-CoV-2 variants. These data suggest that the standard COVID-19 mRNA vaccine regimens will likely not provide optimal protection in immunocompromised individuals.
Individuals on immunosuppression for various indications have impaired neutralizing, binding, and nonneutralizing antibody responses and reduced T-cell activity in response to COVID-19 mRNA vaccination compared to immunocompetent controls. This suggests that standard vaccination may not result in protective immunity in this population.
Antibody transfer via breastmilk represents an evolutionary strategy to boost immunity in early life. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies have ...been observed in the breastmilk, the functional quality of these antibodies remains unclear. Here, we apply systems serology to characterize SARS-CoV-2-specific antibodies in maternal serum and breastmilk to compare the functional characteristics of antibodies in these fluids. Distinct SARS-CoV-2-specific antibody responses are observed in the serum and breastmilk of lactating individuals previously infected with SARS-CoV-2, with a more dominant transfer of immunoglobulin A (IgA) and IgM into breastmilk. Although IgGs are present in breastmilk, they are functionally attenuated. We observe preferential transfer of antibodies capable of eliciting neutrophil phagocytosis and neutralization compared to other functions, pointing to selective transfer of certain functional antibodies to breastmilk. These data highlight the preferential transfer of SARS-CoV-2-specific IgA and IgM to breastmilk, accompanied by select IgG subpopulations, positioned to create a non-pathologic but protective barrier against coronavirus disease 2019 (COVID-19).
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•SARS-CoV-2 induces pathogen-specific antibodies in maternal blood and breastmilk•Breastmilk antibodies are functionally attenuated compared to serum antibodies•Neutrophil phagocytosis and neutralization are preferentially present in breastmilk•Disease severity, but not time since symptom onset, impacts transfer to breastmilk
Pullen et al. characterize the functionality of SARS-CoV-2-specific antibodies in maternal blood and breastmilk after SARS-CoV-2 infection. Although infection elicits polyfunctional IgG in blood, breastmilk mostly contains neutralizing and neutrophil-activating IgA, IgM, and IgG, suggesting a selection of specific, non-inflammatory antibody subsets in the breastmilk.
Coronavirus disease 2019 (COVID‐19) is associated with adverse outcomes, including need for invasive mechanical ventilation and death in people with risk factors. Liver enzyme elevation is commonly ...seen in this group, but its clinical significance remains elusive. In this study, we calculated the Fibrosis‐4 (FIB‐4) score for a cohort of hospitalized patients with COVID‐19 and assessed its association with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) RNA, inflammatory cytokine levels, and clinical outcome. A total of 202 hospitalized participants who tested positive for SARS‐CoV‐2 by nasopharyngeal sampling were included in this analysis. FIB‐4 was calculated for each participant using the alanine aminotransferase, aspartate aminotransferase, age, and platelet count. We evaluated the association between FIB‐4 and mortality using both multivariate logistic regression and Cox proportional hazards model. Correlations between FIB‐4 and SARS‐CoV‐2 RNA and cytokine levels were evaluated using the Spearman test. Among the 202 participants, 22 died. The median FIB‐4 in participants who survived and died were 1.91 and 3.98 (
P
< 0.001 by Mann‐Whitney U test), respectively. Each one‐unit increment in FIB‐4 was associated with an increased odds of death (odds ratio, 1.79; 95% confidence interval, 1.36, 2.35;
P
< 0.001) after adjusting for baseline characteristics including sex, body mass index, hypertension, diabetes, and history of liver diseases. During hospitalization, FIB‐4 peaked and then normalized in the survival group but failed to normalize in the death group. FIB‐4 was positively correlated with the level of SARS‐CoV‐2 viral load and monocyte‐associated cytokines, especially interleukin‐6 and interferon gamma–induced protein 10.
Conclusion:
FIB‐4 is associated with mortality in COVID‐19, independent of underlying conditions including liver diseases. FIB‐4 may be a simple and inexpensive approach to risk‐stratify individuals with COVID‐19.
Adjuvanted soluble protein vaccines have been used extensively in humans for protection against various viral infections based on their robust induction of antibody responses. Here, soluble ...prefusion-stabilized spike protein trimers (preS dTM) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were formulated with the adjuvant AS03 and administered twice to nonhuman primates (NHPs). Binding and functional neutralization assays and systems serology revealed that the vaccinated NHP developed AS03-dependent multifunctional humoral responses that targeted distinct domains of the spike protein and bound to a variety of Fc receptors mediating immune cell effector functions in vitro. The neutralizing 50% inhibitory concentration titers for pseudovirus and live SARS-CoV-2 were higher than titers for a panel of human convalescent serum samples. NHPs were challenged intranasally and intratracheally with a high dose (3 × 10
plaque forming units) of SARS-CoV-2 (USA-WA1/2020 isolate). Two days after challenge, vaccinated NHPs showed rapid control of viral replication in both the upper and lower airways. Vaccinated NHPs also had increased spike protein-specific immunoglobulin G (IgG) antibody responses in the lung as early as 2 days after challenge. Moreover, passive transfer of vaccine-induced IgG to hamsters mediated protection from subsequent SARS-CoV-2 challenge. These data show that antibodies induced by the AS03-adjuvanted preS dTM vaccine were sufficient to mediate protection against SARS-CoV-2 in NHPs and that rapid anamnestic antibody responses in the lung may be a key mechanism for protection.
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