Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 52
Filter
1.
Am J Obstet Gynecol ; 2022 Jul 19.
Article in English | MEDLINE | ID: covidwho-1935983

ABSTRACT

BACKGROUND: While emerging data during the SARS-CoV-2 pandemic have demonstrated robust mRNA 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 mRNA vaccine booster doses. Whether all populations, including pregnant and lactating individuals, will mount a comparable response to a booster dose is not known. OBJECTIVE: We sought to profile the humoral immune response to a COVID-19 mRNA booster dose in a cohort of pregnant, lactating, and age-matched nonpregnant women. STUDY DESIGN: We 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 mRNA-1273 booster dose after primary COVID-19 vaccination. We also examined the vaccine-induced antibody profiles of 15 maternal:cord dyads at delivery. RESULTS: Receipt of a booster dose during pregnancy resulted in increased IgG1 against Omicron Spike (post-primary vaccination vs post-booster, p = 0.03). Pregnant and lactating individuals exhibited equivalent Spike-specific total IgG1, IgM and IgA levels and neutralizing titers against Omicron compared to nonpregnant women. Subtle differences in Fc-receptor binding and antibody subclass profiles were observed in the immune response to a booster dose in pregnant compared to nonpregnant individuals. Analysis of maternal and cord antibody profiles at delivery demonstrated equivalent total Spike-specific IgG1 in maternal and cord blood, yet higher Spike-specific FcγR3a-binding antibodies in the cord relative to maternal blood (p = 0.002), consistent with preferential transfer of highly functional IgG. Spike-specific IgG1 levels in the cord were positively correlated with time elapsed since receipt of the booster dose (Spearman R 0.574, p = 0.035). CONCLUSIONS: These data suggest that receipt of a booster dose during pregnancy induces a robust Spike-specific humoral immune response, including against Omicron. If boosting occurs in the third trimester, higher Spike-specific cord IgG1 levels are achieved with greater time elapsed between receipt of the booster and delivery. Receipt of a booster dose has the potential to augment maternal and neonatal immunity.

2.
Nat Commun ; 13(1): 3571, 2022 06 28.
Article in English | MEDLINE | ID: covidwho-1908170

ABSTRACT

The availability of three COVID-19 vaccines in the United States provides an unprecedented opportunity to examine how vaccine platforms and timing of vaccination in pregnancy impact maternal and neonatal immunity. Here, we characterize the antibody profile after Ad26.COV2.S, mRNA-1273 or BNT162b2 vaccination in 158 pregnant individuals and evaluate transplacental antibody transfer by profiling maternal and umbilical cord blood in 175 maternal-neonatal dyads. These analyses reveal lower vaccine-induced functions and Fc receptor-binding after Ad26.COV2.S compared to mRNA vaccination and subtle advantages in titer and function with mRNA-1273 versus BN162b2. mRNA vaccines have higher titers and functions against SARS-CoV-2 variants of concern. First and third trimester vaccination results in enhanced maternal antibody-dependent NK-cell activation, cellular and neutrophil phagocytosis, and complement deposition relative to second trimester. Higher transplacental transfer ratios following first and second trimester vaccination may reflect placental compensation for waning maternal titers. These results provide novel insight into the impact of platform and trimester of vaccination on maternal humoral immune response and transplacental antibody transfer.


Subject(s)
COVID-19 , Pregnancy Complications, Infectious , Ad26COVS1 , Antibodies, Viral , BNT162 Vaccine , COVID-19/prevention & control , COVID-19 Vaccines , Female , Humans , Immunity , Infant, Newborn , Placenta , Pregnancy , Pregnancy Complications, Infectious/prevention & control , SARS-CoV-2 , United States , Vaccination/methods
3.
Am J Obstet Gynecol ; 2022 Apr 14.
Article in English | MEDLINE | ID: covidwho-1872911

ABSTRACT

BACKGROUND: SARS-CoV-2 infection is associated with enhanced disease severity in pregnant women. Despite the potential of COVID-19 vaccines to reduce severe disease, vaccine uptake remained relatively low among pregnant women. Just as coordinated messaging from the Centers for Disease Control and Prevention and leading obstetrics organizations began to increase vaccine confidence in this vulnerable group, the evolution of SARS-CoV-2 variants of concerns, including the Omicron variant, raised new concerns about vaccine efficacy because of their ability to escape vaccine-induced neutralizing antibodies. Early data point to a milder disease course following infection with the Omicron variant in vaccinated individuals. Thus, these data suggest that alternate vaccine-induced immunity beyond neutralization may continue to attenuate Omicron variant-induced disease, such as Fc-mediated antibody activity. OBJECTIVE: This study aimed to test whether vaccine-induced antibodies raised during pregnancy continue to bind to and leverage Fc receptors to protect against variants of concern including the Omicron variant. STUDY DESIGN: The receptor binding domain or whole spike-specific antibody isotype binding titers and Fc gamma receptor binding directed toward variants of concern, including the Omicron variant, were analyzed in pregnant women after receiving the full dose regimen of either the Pfizer/BioNTech BNT62b2 (n=10) or Moderna mRNA-1273 (n=10) vaccination using a multiplexing Luminex assay. RESULTS: Reduced isotype recognition of the Omicron receptor binding domain was observed following administration of either vaccine with relatively preserved, albeit reduced, recognition of the whole Omicron spike by immunoglobulin M and G antibodies. Despite the near complete loss of Fc receptor binding to the Omicron receptor binding domain, Fc receptor binding to the Omicron spike was more variable but largely preserved. CONCLUSION: Reduced binding titers to the Omicron receptor binding domain aligns with the observed loss of neutralizing activity. Despite the loss of neutralization, preserved, albeit reduced, Omicron spike recognition and Fc receptor binding potentially continue to attenuate disease severity in pregnant women.

4.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-336971

ABSTRACT

BACKGROUND While emerging data during the SARS-CoV-2 pandemic have demonstrated robust mRNA 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 mRNA vaccine booster doses. Whether all populations, including pregnant and lactating individuals, will mount a comparable response to a booster dose is not known. OBJECTIVE We sought to profile the humoral immune response to a COVID-19 mRNA booster dose in a cohort of pregnant, lactating, and age-matched nonpregnant women. STUDY DESIGN We 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 mRNA-1273 booster dose after primary COVID-19 vaccination. We also examined the vaccine-induced antibody profiles of 15 maternal:cord dyads at delivery. RESULTS Receipt of a booster dose during pregnancy resulted in increased IgG1 against Omicron Spike (post-primary vaccination vs post-booster, p = 0.03). Pregnant and lactating individuals exhibited equivalent Spike-specific total IgG1, IgM and IgA levels and neutralizing titers against Omicron compared to nonpregnant women. Subtle differences in Fc-receptor binding and antibody subclass profiles were observed in the immune response to a booster dose in pregnant compared to nonpregnant individuals. Analysis of maternal and cord antibody profiles at delivery demonstrated equivalent total Spike-specific IgG1 in maternal and cord blood, yet higher Spike-specific FcγR3a-binding antibodies in the cord relative to maternal blood (p = 0.002), consistent with preferential transfer of highly functional IgG. Spike-specific IgG1 levels in the cord were positively correlated with time elapsed since receipt of the booster dose (Spearman R 0.574, p = 0.035). CONCLUSIONS These data suggest that receipt of a booster dose during pregnancy induces a robust Spike-specific humoral immune response, including against Omicron. If boosting occurs in the third trimester, higher Spike-specific cord IgG1 levels are achieved with greater time elapsed between receipt of the booster and delivery. Receipt of a booster dose has the potential to augment maternal and neonatal immunity.

5.
J Infect Dis ; 225(7): 1124-1128, 2022 Apr 01.
Article in English | MEDLINE | ID: covidwho-1774388

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.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Immunogenicity, Vaccine , RNA, Messenger , Vaccines, Synthetic
7.
Sci Transl Med ; 14(638): eabm4996, 2022 03 30.
Article in English | MEDLINE | ID: covidwho-1705843

ABSTRACT

Ad26.COV2.S has demonstrated durability and clinical efficacy against symptomatic COVID-19 in humans. In this study, we report the correlates of durability of humoral and cellular immune responses in 20 rhesus macaques immunized with single-shot Ad26.COV2.S and the immunogenicity of a booster shot at 8 to 10 months after the initial immunization. Ad26.COV2.S elicited durable binding and neutralizing antibodies as well as memory B cells and long-lived bone marrow plasma cells. Innate immune responses and bone marrow plasma cell responses correlated with durable antibody responses. After Ad26.COV2.S boost immunization, binding and neutralizing antibody responses against multiple SARS-CoV-2 variants increased 31- to 69-fold and 23- to 43-fold, respectively, compared with preboost concentrations. Antigen-specific B cell and T cell responses also increased substantially after the boost immunization. Boosting with a modified Ad26.COV2.S.351 vaccine expressing the SARS-CoV-2 spike protein from the beta variant led to largely comparable responses with slightly higher beta- and omicron-specific humoral immune responses. These data demonstrate that a late boost with Ad26.COV2.S or Ad26.COV2.S.351 resulted in a marked increase in humoral and cellular immune responses that were highly cross-reactive across multiple SARS-CoV-2 variants in rhesus macaques.


Subject(s)
Ad26COVS1 , COVID-19 , Immunity, Humoral , Immunization, Secondary , SARS-CoV-2 , Ad26COVS1/immunology , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , Macaca mulatta , Spike Glycoprotein, Coronavirus
8.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-319421

ABSTRACT

Antibody transfer via breastmilk represents an evolutionary strategy to boost immunity in early life. Although SARS-CoV-2-specific antibodies have been observed in the breastmilk of mothers with COVID-19, the functional quality of these antibodies remains unclear. Here, we applied systems serology to characterize SARS-CoV-2-specific antibodies in maternal serum and breastmilk to define the mechanism of antibody transfer into breastmilk. Distinct SARS-CoV-2-specific antibody responses were observed in the serum and breastmilk of lactating individuals previously infected with SARS-CoV-2, with a dominant transfer of both IgA and IgM into breastmilk. A spike-specific functional IgG were present in breastmilk, breastmilk IgGs were functionally attenuated. Breastmilk antibodies were less inflammatory than maternal serum antibodies, pointing to a sieve offunctional antibodies to breastmilk. These data highlight the preferential breastmilk transfer of SARS-CoV-2-specific IgA and IgM to neonates, accompanied by selected subpopulations of IgG, positioned to create a non-pathologic, but highly protective barrier against COVID-19 disease.Funding Statement: This work was supported by by NHLBI (grants K08HL1469630-02 and K08HL146963-02S1, to KJG), the National Science Foundation Graduate Research Fellowship under Grant No. (#1745302, to KMP), the NIH (U19 AI142790, U19 AI135995, R37AI080289), the Massachusetts Consortium on Pathogen Readiness (MassCPR). Declaration of Interests: G.A. is the founder of Seromyx. K.J.G. has consulted for BillionToOne, Illumina, and Aetion. INCOMPLETE Ethics Approval Statement: This study was approved by the MGH-BWH Institutional Review Board and the BIDMC Institutional Review Board.

9.
mBio ; : e0214121, 2022 Jan 25.
Article in English | MEDLINE | ID: covidwho-1650754

ABSTRACT

As public health guidelines throughout the world have relaxed in response to vaccination campaigns against SARS-CoV-2, it is likely that SARS-CoV-2 will remain endemic, fueled by the rise of more infectious SARS-CoV-2 variants. Moreover, in the setting of waning natural and vaccine immunity, reinfections have emerged across the globe, even among previously infected and vaccinated individuals. As such, the ability to detect reexposure to and reinfection by SARS-CoV-2 is a key component for global protection against this virus and, more importantly, against the potential emergence of vaccine escape mutations. Accordingly, there is a strong and continued need for the development and deployment of simple methods to detect emerging hot spots of reinfection to inform targeted pandemic response and containment, including targeted and specific deployment of vaccine booster campaigns. In this study, we identify simple, rapid immune biomarkers of reinfection in rhesus macaques, including IgG3 antibody levels against nucleocapsid and FcγR2A receptor binding activity of anti-RBD antibodies, that are recapitulated in human reinfection cases. As such, this cross-species analysis underscores the potential utility of simple antibody titers and function as price-effective and scalable markers of reinfection to provide increased resolution and resilience against new outbreaks. IMPORTANCE As public health and social distancing guidelines loosen in the setting of waning global natural and vaccine immunity, a deeper understanding of the immunological response to reexposure and reinfection to this highly contagious pathogen is necessary to maintain public health. Viral sequencing analysis provides a robust but unrealistic means to monitor reinfection globally. The identification of scalable pathogen-specific biomarkers of reexposure and reinfection, however, could significantly accelerate our capacity to monitor the spread of the virus through naive and experienced hosts, providing key insights into mechanisms of disease attenuation. Using a nonhuman primate model of controlled SARS-CoV-2 reexposure, we deeply probed the humoral immune response following rechallenge with various doses of viral inocula. We identified virus-specific humoral biomarkers of reinfection, with significant increases in antibody titer and function upon rechallenge across a range of humoral features, including IgG1 to the receptor binding domain of the spike protein of SARS-CoV-2 (RBD), IgG3 to the nucleocapsid protein (N), and FcγR2A receptor binding to anti-RBD antibodies. These features not only differentiated primary infection from reexposure and reinfection in monkeys but also were recapitulated in a sequencing-confirmed reinfection patient and in a cohort of putatively reinfected humans that evolved a PCR-positive test in spite of preexisting seropositivity. As such, this cross-species analysis using a controlled primate model and human cohorts reveals increases in antibody titers as promising cross-validated serological markers of reinfection and reexposure.

10.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-293111

ABSTRACT

COVID-19 vaccination in pregnancy generates functional anti-Spike IgG antibodies that are known to cross the placenta. However, the durability of vaccine-induced maternal anti-S IgG in infant circulation, and how it compares to durability of antibody from maternal natural infection, is unknown. We quantified anti-S IgG in 92 2-month and 6-month-old infants whose mothers were vaccinated in pregnancy, and in 12 6-month-old infants after maternal natural infection with SARS-CoV-2. In the vaccinated group, 94% (58/62) of infants had detectable anti-S IgG at 2 months, and 60% (18/30) had detectable antibody at 6 months. In contrast, 8% (1/12) of infants born to women infected with SARS-CoV-2 in pregnancy had detectable anti-S IgG at the 6-month timepoint. Vaccination resulted in significantly higher maternal and cord titers at delivery and significantly greater antibody persistence in infants at 6 months, compared to natural infection.

11.
Sci Transl Med ; 13(617): eabi8631, 2021 Oct 27.
Article in English | MEDLINE | ID: covidwho-1532951

ABSTRACT

Substantial immunological changes occur throughout pregnancy to render the mother immunologically tolerant to the fetus and allow fetal growth. However, additional local and systemic immunological adaptations also occur, allowing the maternal immune system to continue to protect the dyad against pathogens both during pregnancy and after birth through lactation. This fine balance of tolerance and immunity, along with physiological and hormonal changes, contributes to increased susceptibility to particular infections in pregnancy, including more severe coronavirus disease 2019 (COVID-19). Whether these changes also make pregnant women less responsive to vaccination or induce altered immune responses to vaccination remains incompletely understood. To define potential changes in vaccine response during pregnancy and lactation, we undertook deep sequencing of the humoral vaccine response in a group of pregnant and lactating women and nonpregnant age-matched controls. Vaccine-specific titers were comparable between pregnant women, lactating women, and nonpregnant controls. However, Fc receptor (FcR) binding and antibody effector functions were induced with delayed kinetics in both pregnant and lactating women compared with nonpregnant women after the first vaccine dose, which normalized after the second dose. Vaccine boosting resulted in high FcR-binding titers in breastmilk. These data suggest that pregnancy promotes resistance to generating proinflammatory antibodies and indicates that there is a critical need to follow prime-boost timelines in this vulnerable population to ensure full immunity is attained.


Subject(s)
COVID-19 Vaccines , COVID-19 , Female , Humans , Lactation , Pregnancy , RNA, Messenger , SARS-CoV-2
13.
J Infect Dis ; 225(7): 1124-1128, 2022 Apr 01.
Article in English | MEDLINE | ID: covidwho-1522222

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.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Immunogenicity, Vaccine , RNA, Messenger , Vaccines, Synthetic
14.
Viruses ; 13(11)2021 11 06.
Article in English | MEDLINE | ID: covidwho-1502534

ABSTRACT

Obesity is a key correlate of severe SARS-CoV-2 outcomes while the role of obesity on risk of SARS-CoV-2 infection, symptom phenotype, and immune response remain poorly defined. We examined data from a prospective SARS-CoV-2 cohort study to address these questions. Serostatus, body mass index, demographics, comorbidities, and prior COVID-19 compatible symptoms were assessed at baseline and serostatus and symptoms monthly thereafter. SARS-CoV-2 immunoassays included an IgG ELISA targeting the spike RBD, multiarray Luminex targeting 20 viral antigens, pseudovirus neutralization, and T cell ELISPOT assays. Our results from a large prospective SARS-CoV-2 cohort study indicate symptom phenotype is strongly influenced by obesity among younger but not older age groups; we did not identify evidence to suggest obese individuals are at higher risk of SARS-CoV-2 infection; and remarkably homogenous immune activity across BMI categories suggests immune protection across these groups may be similar.


Subject(s)
Antibodies, Viral/blood , COVID-19/complications , COVID-19/immunology , Obesity/complications , Obesity/immunology , Spike Glycoprotein, Coronavirus/immunology , Adolescent , Adult , Age Factors , Body Mass Index , COVID-19/epidemiology , COVID-19/physiopathology , Female , Humans , Immunoglobulin G/blood , Male , Middle Aged , Risk Factors , SARS-CoV-2/immunology , Young Adult
15.
Cell Rep ; 37(6): 109959, 2021 11 09.
Article in English | MEDLINE | ID: covidwho-1474393

ABSTRACT

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).


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , Milk, Human/immunology , SARS-CoV-2/immunology , Antibody Formation/immunology , Female , Humans , Immunoglobulin Isotypes/immunology , Lactation/immunology , Pregnancy , Pregnancy Complications, Infectious/immunology , Spike Glycoprotein, Coronavirus/immunology
16.
Sci Transl Med ; 13(617): eabi7428, 2021 Oct 27.
Article in English | MEDLINE | ID: covidwho-1476378

ABSTRACT

There is a persistent bias toward higher prevalence and increased severity of coronavirus disease 2019 (COVID-19) in males. Underlying mechanisms accounting for this sex difference remain incompletely understood. Interferon responses have been implicated as a modulator of COVID-19 disease in adults and play a key role in the placental antiviral response. Moreover, the interferon response has been shown to alter Fc receptor expression and therefore may affect placental antibody transfer. Here, we examined the intersection of maternal-fetal antibody transfer, viral-induced placental interferon responses, and fetal sex in pregnant women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Placental Fc receptor abundance, interferon-stimulated gene (ISG) expression, and SARS-CoV-2 antibody transfer were interrogated in 68 human pregnancies. Sexually dimorphic expression of placental Fc receptors, ISGs and proteins, and interleukin-10 was observed after maternal SARS-CoV-2 infection, with up-regulation of these features in placental tissue of pregnant individuals with male fetuses. Reduced maternal SARS-CoV-2­specific antibody titers and impaired placental antibody transfer were also observed in pregnancies with a male fetus. These results demonstrate fetal sex-specific maternal and placental adaptive and innate immune responses to SARS-CoV-2.


Subject(s)
COVID-19 , Pregnancy Complications, Infectious , Female , Humans , Immunity , Infectious Disease Transmission, Vertical , Placenta , Pregnancy , SARS-CoV-2
17.
Res Sq ; 2021 Feb 15.
Article in English | MEDLINE | ID: covidwho-1417405

ABSTRACT

Recently approved vaccines have already shown remarkable protection in limiting SARS-CoV-2 associated disease. However, immunologic mechanism(s) of protection, as well as how boosting alters immunity to wildtype and newly emerging strains, remain incompletely understood. Here we deeply profiled the humoral immune response in a cohort of non-human primates immunized with a stable recombinant full-length SARS-CoV-2 spike (S) glycoprotein (NVX-CoV2373) at two dose levels, administered as a single or two-dose regimen with a saponin-based adjuvant Matrix-M™. While antigen dose had some effect on Fc-effector profiles, both antigen dose and boosting significantly altered overall titers, neutralization and Fc-effector profiles, driving unique vaccine-induced antibody fingerprints. Combined differences in antibody effector functions and neutralization were strongly associated with distinct levels of protection in the upper and lower respiratory tract, pointing to the presence of combined, but distinct, compartment-specific neutralization and Fc-mechanisms as key determinants of protective immunity against infection. Moreover, NVX-CoV2373 elicited antibodies functionally target emerging SARS-CoV-2 variants, collectively pointing to the critical collaborative role for Fab and Fc in driving maximal protection against SARS-CoV-2. Collectively, the data presented here suggest that a single dose may prevent disease, but that two doses may be essential to block further transmission of SARS-CoV-2 and emerging variants.

18.
Nat Commun ; 12(1): 3587, 2021 06 11.
Article in English | MEDLINE | ID: covidwho-1387350

ABSTRACT

There is a great need for the development of vaccines that induce potent and long-lasting protective immunity against SARS-CoV-2. Multimeric display of the antigen combined with potent adjuvant can enhance the potency and longevity of the antibody response. The receptor binding domain (RBD) of the spike protein is a primary target of neutralizing antibodies. Here, we developed a trimeric form of the RBD and show that it induces a potent neutralizing antibody response against live virus with diverse effector functions and provides protection against SARS-CoV-2 challenge in mice and rhesus macaques. The trimeric form induces higher neutralizing antibody titer compared to monomer with as low as 1µg antigen dose. In mice, adjuvanting the protein with a TLR7/8 agonist formulation alum-3M-052 induces 100-fold higher neutralizing antibody titer and superior protection from infection compared to alum. SARS-CoV-2 infection causes significant loss of innate cells and pathology in the lung, and vaccination protects from changes in innate cells and lung pathology. These results demonstrate RBD trimer protein as a suitable candidate for vaccine against SARS-CoV-2.


Subject(s)
Adjuvants, Immunologic/administration & dosage , COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , Heterocyclic Compounds, 3-Ring/administration & dosage , Stearic Acids/administration & dosage , Alum Compounds/administration & dosage , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antibody Formation/immunology , COVID-19 Vaccines/administration & dosage , Disease Models, Animal , Heterocyclic Compounds, 3-Ring/immunology , Humans , Macaca mulatta , Mice , Protein Binding , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/immunology , Stearic Acids/immunology
19.
Cell ; 184(3): 628-642.e10, 2021 02 04.
Article in English | MEDLINE | ID: covidwho-1385216

ABSTRACT

SARS-CoV-2 infection causes more severe disease in pregnant women compared to age-matched non-pregnant women. Whether maternal infection causes changes in the transfer of immunity to infants remains unclear. Maternal infections have previously been associated with compromised placental antibody transfer, but the mechanism underlying this compromised transfer is not established. Here, we used systems serology to characterize the Fc profile of influenza-, pertussis-, and SARS-CoV-2-specific antibodies transferred across the placenta. Influenza- and pertussis-specific antibodies were actively transferred. However, SARS-CoV-2-specific antibody transfer was significantly reduced compared to influenza- and pertussis-specific antibodies, and cord titers and functional activity were lower than in maternal plasma. This effect was only observed in third-trimester infection. SARS-CoV-2-specific transfer was linked to altered SARS-CoV-2-antibody glycosylation profiles and was partially rescued by infection-induced increases in IgG and increased FCGR3A placental expression. These results point to unexpected compensatory mechanisms to boost immunity in neonates, providing insights for maternal vaccine design.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , Immunoglobulin G/immunology , Maternal-Fetal Exchange/immunology , Placenta/immunology , Pregnancy Complications, Infectious/immunology , SARS-CoV-2/immunology , Adult , Female , Humans , Infant, Newborn , Pregnancy , Pregnancy Trimester, Third/immunology , Receptors, IgG/immunology , THP-1 Cells
20.
Cell Rep Med ; 2(9): 100405, 2021 09 21.
Article in English | MEDLINE | ID: covidwho-1377862

ABSTRACT

Recently approved vaccines have shown remarkable efficacy in limiting SARS-CoV-2-associated disease. However, with the variety of vaccines, immunization strategies, and waning antibody titers, defining the correlates of immunity across a spectrum of antibody titers is urgently required. Thus, we profiled the humoral immune response in a cohort of non-human primates immunized with a recombinant SARS-CoV-2 spike glycoprotein (NVX-CoV2373) at two doses, administered as a single- or two-dose regimen. Both antigen dose and boosting significantly altered neutralization titers and Fc-effector profiles, driving unique vaccine-induced antibody fingerprints. Combined differences in antibody effector functions and neutralization were associated with distinct levels of protection in the upper and lower respiratory tract. Moreover, NVX-CoV2373 elicited antibodies that functionally targeted emerging SARS-CoV-2 variants. Collectively, the data presented here suggest that a single dose may prevent disease via combined Fc/Fab functions but that two doses may be essential to block further transmission of SARS-CoV-2 and emerging variants.


Subject(s)
COVID-19 Vaccines/immunology , SARS-CoV-2/immunology , Saponins/immunology , Animals , Antibodies, Neutralizing/drug effects , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/virology , Dose-Response Relationship, Immunologic , Female , Immunity, Humoral/immunology , Immunogenicity, Vaccine , Immunoglobulin Fab Fragments/immunology , Immunoglobulin Fc Fragments/immunology , Macaca mulatta , Male , Nanoparticles , Primates/immunology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus , Vaccination
SELECTION OF CITATIONS
SEARCH DETAIL