Try a new search

Format these results:

Searched for:

person:mullim04

in-biosketch:true

Total Results:

151


Cellular and Humoral Immunity to SARS-CoV-2 Infection in Multiple Sclerosis Patients on Ocrelizumab and Other Disease-Modifying Therapies: A Multi-Ethnic Observational Study

Kister, Ilya; Patskovsky, Yury; Curtin, Ryan; Pei, Jinglan; Perdomo, Katherine; Rimler, Zoe; Voloshyna, Iryna; Samanovic, Marie I; Cornelius, Amber R; Velmurugu, Yogambigai; Nyovanie, Samantha; Kim, Joseph J; Tardio, Ethan; Bacon, Tamar E; Zhovtis Ryerson, Lana; Raut, Pranil; Pedotti, Rosetta; Hawker, Kathleen; Raposo, Catarina; Priest, Jessica; Cabatingan, Mark; Winger, Ryan C; Mulligan, Mark J; Krogsgaard, Michelle; Silverman, Gregg J
OBJECTIVE:The objective of this study was to determine the impact of multiple sclerosis (MS) disease-modifying therapies (DMTs) on the development of cellular and humoral immunity to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection. METHODS:Patients with MS aged 18 to 60 years were evaluated for anti-nucleocapsid and anti-Spike receptor-binding domain (RBD) antibody with electro-chemiluminescence immunoassay; antibody responses to Spike protein, RBD, N-terminal domain with multiepitope bead-based immunoassays (MBI); live virus immunofluorescence-based microneutralization assay; T-cell responses to SARS-CoV-2 Spike using TruCulture enzyme-linked immunosorbent assay (ELISA); and IL-2 and IFNγ ELISpot assays. Assay results were compared by DMT class. Spearman correlation and multivariate analyses were performed to examine associations between immunologic responses and infection severity. RESULTS:Between January 6, 2021, and July 21, 2021, 389 patients with MS were recruited (mean age 40.3 years; 74% women; 62% non-White). Most common DMTs were ocrelizumab (OCR)-40%; natalizumab -17%, Sphingosine 1-phosphate receptor (S1P) modulators -12%; and 15% untreated. One hundred seventy-seven patients (46%) had laboratory evidence of SARS-CoV-2 infection; 130 had symptomatic infection, and 47 were asymptomatic. Antibody responses were markedly attenuated in OCR compared with other groups (p ≤0.0001). T-cell responses (IFNγ) were decreased in S1P (p = 0.03), increased in natalizumab (p <0.001), and similar in other DMTs, including OCR. Cellular and humoral responses were moderately correlated in both OCR (r = 0.45, p = 0.0002) and non-OCR (r = 0.64, p <0.0001). Immune responses did not differ by race/ethnicity. Coronavirus disease 2019 (COVID-19) clinical course was mostly non-severe and similar across DMTs; 7% (9/130) were hospitalized. INTERPRETATION/CONCLUSIONS:DMTs had differential effects on humoral and cellular immune responses to SARS-CoV-2 infection. Immune responses did not correlate with COVID-19 clinical severity in this relatively young and nondisabled group of patients with MS. ANN NEUROL 2022.
PMID: 35289960
ISSN: 1531-8249
CID: 5191732

Methotrexate and TNF inhibitors affect long-term immunogenicity to COVID-19 vaccination in patients with immune-mediated inflammatory disease

Haberman, Rebecca H; Um, Seungha; Axelrad, Jordan E; Blank, Rebecca B; Uddin, Zakwan; Catron, Sydney; Neimann, Andrea L; Mulligan, Mark J; Herat, Ramin Sedaghat; Hong, Simon J; Chang, Shannon; Myrtaj, Arnold; Ghiasian, Ghoncheh; Izmirly, Peter M; Saxena, Amit; Solomon, Gary; Azar, Natalie; Samuels, Jonathan; Golden, Brian D; Rackoff, Paula; Adhikari, Samrachana; Hudesman, David P; Scher, Jose U
PMCID:8975261
PMID: 35403000
ISSN: 2665-9913
CID: 5218902

Low incidence and transient elevation of autoantibodies post mRNA COVID-19 vaccination in inflammatory arthritis

Blank, Rebecca B; Haberman, Rebecca H; Qian, Kun; Samanovic, Marie; Castillo, Rochelle; Jimenez Hernandez, Anthony; Vasudevapillai Girija, Parvathy; Catron, Sydney; Uddin, Zakwan; Rackoff, Paula; Solomon, Gary; Azar, Natalie; Rosenthal, Pamela; Izmirly, Peter; Samuels, Jonathan; Golden, Brian; Reddy, Soumya; Mulligan, Mark J; Hu, Jiyuan; Scher, Jose U
OBJECTIVES/OBJECTIVE:Autoantibody seroconversion has been extensively studied in the context of COVID-19 infection but data regarding post-vaccination autoantibody production is lacking. Here we aimed to determine the incidence of common autoantibody formation following mRNA COVID-19 vaccines in patients with inflammatory arthritis (IA) and in healthy controls. METHODS:Autoantibody seroconversion was measured by serum ELISA in a longitudinal cohort of IA participants and healthy controls before and after COVID-19 mRNA-based immunization. RESULTS:Overall, there was a significantly lower incidence of ANA seroconversion in participants who did not contract COVID-19 prior to vaccination compared with those who been previously infected (7.4% vs 24.1%, p= 0.014). Incidence of de novo anti-cyclic citrullinated protein (CCP) seroconversion in all participants was low at 4.9%. Autoantibody levels were typically of low titer, transient, and not associated with increase in IA flares. CONCLUSIONS:In both health and inflammatory arthritis, the risk of autoantibody seroconversion is lower following mRNA-based immunization than following natural SARS-CoV-2 infection. Importantly, seroconversion does not correlate with self-reported IA disease flare risk, further supporting the encouragement of mRNA-based COVID-19 immunization in the IA population.
PMID: 35640110
ISSN: 1462-0332
CID: 5235902

Increased resistance of SARS-CoV-2 Omicron variant to neutralization by vaccine-elicited and therapeutic antibodies

Tada, Takuya; Zhou, Hao; Dcosta, Belinda M; Samanovic, Marie I; Chivukula, Vidya; Herati, Ramin S; Hubbard, Stevan R; Mulligan, Mark J; Landau, Nathaniel R
BACKGROUND:SARS-CoV-2 vaccines currently authorized for emergency use have been highly successful in preventing infection and lessening disease severity. The vaccines maintain effectiveness against earlier SARS-CoV-2 Variants of Concern but the heavily mutated, highly transmissible Omicron variant presents an obstacle both to vaccine protection and monoclonal antibody therapies. METHODS:Pseudotyped lentiviruses were incubated with serum from vaccinated and boosted donors or therapeutic monoclonal antibody and then applied to target cells. After 2 days, luciferase activity was measured in a microplate luminometer. Resistance mutations of the Omicron spike were identified using point-mutated spike protein pseudotypes and mapped onto the three-dimensional spike protein structure. FINDINGS/RESULTS:Virus with the Omicron spike protein was 26-fold resistant to neutralization by recovered donor sera and 26-34-fold resistance to Pfizer BNT162b2 and Moderna vaccine-elicited antibodies following two immunizations. A booster immunization increased neutralizing titres against Omicron. Neutralizing titres against Omicron were increased in the sera with a history of prior SARS-CoV-2 infection. Analysis of the therapeutic monoclonal antibodies showed that the Regeneron and Eli Lilly monoclonal antibodies were ineffective against the Omicron pseudotype while Sotrovimab and Evusheld were partially effective. INTERPRETATION/CONCLUSIONS:The results highlight the benefit of a booster immunization to protect against the Omicron variant and demonstrate the challenge to monoclonal antibody therapy. The decrease in neutralizing titres against Omicron suggest that much of the vaccine efficacy may rely on T cells. FUNDING/BACKGROUND:The work was funded by grants from the NIH to N.R.L. (DA046100, AI122390 and AI120898) and 55 to M.J.M. (UM1AI148574).
PMCID:9021600
PMID: 35465948
ISSN: 2352-3964
CID: 5205452

Homologous and Heterologous Covid-19 Booster Vaccinations

Atmar, Robert L; Lyke, Kirsten E; Deming, Meagan E; Jackson, Lisa A; Branche, Angela R; El Sahly, Hana M; Rostad, Christina A; Martin, Judith M; Johnston, Christine; Rupp, Richard E; Mulligan, Mark J; Brady, Rebecca C; Frenck, Robert W; Bäcker, Martín; Kottkamp, Angelica C; Babu, Tara M; Rajakumar, Kumaravel; Edupuganti, Srilatha; Dobrzynski, David; Coler, Rhea N; Posavad, Christine M; Archer, Janet I; Crandon, Sonja; Nayak, Seema U; Szydlo, Daniel; Zemanek, Jillian A; Dominguez Islas, Clara P; Brown, Elizabeth R; Suthar, Mehul S; McElrath, M Juliana; McDermott, Adrian B; O'Connell, Sarah E; Montefiori, David C; Eaton, Amanda; Neuzil, Kathleen M; Stephens, David S; Roberts, Paul C; Beigel, John H
BACKGROUND:Although the three vaccines against coronavirus disease 2019 (Covid-19) that have received emergency use authorization in the United States are highly effective, breakthrough infections are occurring. Data are needed on the serial use of homologous boosters (same as the primary vaccine) and heterologous boosters (different from the primary vaccine) in fully vaccinated recipients. METHODS:virus particles, or BNT162b2 (Pfizer-BioNTech) at a dose of 30 μg. The primary end points were safety, reactogenicity, and humoral immunogenicity on trial days 15 and 29. RESULTS:Of the 458 participants who were enrolled in the trial, 154 received mRNA-1273, 150 received Ad26.COV2.S, and 153 received BNT162b2 as booster vaccines; 1 participant did not receive the assigned vaccine. Reactogenicity was similar to that reported for the primary series. More than half the recipients reported having injection-site pain, malaise, headache, or myalgia. For all combinations, antibody neutralizing titers against a SARS-CoV-2 D614G pseudovirus increased by a factor of 4 to 73, and binding titers increased by a factor of 5 to 55. Homologous boosters increased neutralizing antibody titers by a factor of 4 to 20, whereas heterologous boosters increased titers by a factor of 6 to 73. Spike-specific T-cell responses increased in all but the homologous Ad26.COV2.S-boosted subgroup. CD8+ T-cell levels were more durable in the Ad26.COV2.S-primed recipients, and heterologous boosting with the Ad26.COV2.S vaccine substantially increased spike-specific CD8+ T cells in the mRNA vaccine recipients. CONCLUSIONS:Homologous and heterologous booster vaccines had an acceptable safety profile and were immunogenic in adults who had completed a primary Covid-19 vaccine regimen at least 12 weeks earlier. (Funded by the National Institute of Allergy and Infectious Diseases; DMID 21-0012 ClinicalTrials.gov number, NCT04889209.).
PMCID:8820244
PMID: 35081293
ISSN: 1533-4406
CID: 5154552

Dose-Response of a Norovirus GII.2 Controlled Human Challenge Model Inoculum

Rouphael, Nadine; Beck, Allison; Kirby, Amy E; Liu, Pengbo; Natrajan, Muktha S; Lai, Lilin; Phadke, Varun; Winston, Juton; Raabe, Vanessa; Collins, Matthew H; Girmay, Tigisty; Alvarez, Alicarmen; Beydoun, Nour; Karmali, Vinit; Altieri-Rivera, Joanne; Lindesmith, Lisa C; Anderson, Evan J; Wang, Yuke; El-Khorazaty, Jill; Petrie, Carey; Baric, Ralph S; Baqar, Shahida; Moe, Christine L; Mulligan, Mark J
BACKGROUND:Genogroup II noroviruses are the most common cause of acute infectious gastroenteritis. We evaluated the use of a new GII.2 inoculum in a human challenge. METHODS:Forty-four healthy adults (36 secretor-positive and 8 secretor-negative for histo-blood group antigens) were challenged with ascending doses of a new safety-tested Snow Mountain Virus (SMV) GII.2 norovirus inoculum (1.2x10 4 to 1.2x10 7 genomic equivalent copies [GEC]; n=38) or placebo ( n=6). Illness was defined as diarrhea and/or vomiting post challenge in subjects with evidence of infection (defined as GII.2 norovirus RNA detection in stool and/or anti-SMV IgG seroconversion). RESULTS:The highest dose was associated with SMV infection in 90%, and illness in 70% of subjects with 10 of 12 secretor-positive (83%) and 4 of 8 secretor-negative (50%) becoming ill. There was no association between pre-challenge anti-SMV serum IgG concentration, carbohydrate-binding blockade antibody, or salivary IgA and infection. The ID50 was 5.1×10 5 GEC. CONCLUSIONS:High rates of infection and illness were observed in both secretor-positive and negative subjects in this challenge study. However, a high dose will be required to achieve the target of 75% illness to make this an efficient model for evaluating potential norovirus vaccines and therapeutics.
PMID: 35137154
ISSN: 1537-6613
CID: 5176072

Immunogenicity after heterologous third dose COVID-19 vaccination in a heart transplant recipient [Letter]

Mehta, Sapna A; Reyentovich, Alex; Montgomery, Robert A; Segev, Dorry L; Gebel, Howard M; Bray, Robert A; Samanovic, Marie I; Cornelius, Amber R; Mulligan, Mark J; Herati, Ramin S
PMID: 35107835
ISSN: 1399-0012
CID: 5153612

Evaluation of Immune Response and Disease Status in SLE Patients Following SARS-CoV-2 Vaccination

Izmirly, Peter M; Kim, Mimi Y; Samanovic, Marie; Fernandez-Ruiz, Ruth; Ohana, Sharon; Deonaraine, Kristina K; Engel, Alexis J; Masson, Mala; Xie, Xianhong; Cornelius, Amber R; Herati, Ramin S; Haberman, Rebecca H; Scher, Jose U; Guttmann, Allison; Blank, Rebecca B; Plotz, Benjamin; Haj-Ali, Mayce; Banbury, Brittany; Stream, Sara; Hasan, Ghadeer; Ho, Gary; Rackoff, Paula; Blazer, Ashira D; Tseng, Chung-E; Belmont, H Michael; Saxena, Amit; Mulligan, Mark J; Clancy, Robert M; Buyon, Jill P
OBJECTIVE:To evaluate seroreactivity and disease flares after COVID-19 vaccination in a multi-ethnic/racial cohort of patients with systemic lupus erythematosus (SLE). METHODS:90 SLE patients and 20 healthy controls receiving a complete COVID-19 vaccine regimen were included. IgG seroreactivity to the SARS-CoV-2 spike receptor-binding domain (RBD) and SARS-CoV-2 microneutralization were used to evaluate B cell responses; IFN-γ production to assess T cell responses was measured by ELISpot. Disease activity was measured by the hybrid SLE disease activity index (SLEDAI) and flares were assigned by the SELENA/SLEDAI flare index. RESULTS:Overall, fully vaccinated SLE patients produced significantly lower IgG antibodies against SARS-CoV-2 spike RBD than controls. Twenty-six SLE patients (28.8%) generated an IgG response below that of the lowest control (<100 units/ml). In logistic regression analyses, the use of any immunosuppressant or prednisone and a normal anti-dsDNA level prior to vaccination associated with decreased vaccine responses. IgG seroreactivity to the SARS-CoV-2 Spike RBD strongly correlated with the SARS-CoV-2 microneutralization titers and antigen-specific IFN-γ production determined by ELISpot. In a subset of patients with poor antibody responses, IFN-γ production was likewise diminished. Pre-/post-vaccination SLEDAI scores were similar. Only 11.4% of patients had a post-vaccination flare; 1.3% were severe. CONCLUSION/CONCLUSIONS:In a multi-ethnic/racial study of SLE patients 29% had a low response to the COVID-19 vaccine which was associated with being on immunosuppression. Reassuringly, disease flares were rare. While minimal protective levels remain unknown, these data suggest protocol development is needed to assess efficacy of booster vaccination.
PMCID:8426963
PMID: 34347939
ISSN: 2326-5205
CID: 5046532

Neutralization of SARS-CoV-2 Variants by mRNA and Adenoviral Vector Vaccine-Elicited Antibodies

Tada, Takuya; Zhou, Hao; Samanovic, Marie I; Dcosta, Belinda M; Cornelius, Amber; Herati, Ramin S; Mulligan, Mark J; Landau, Nathaniel R
The increasing prevalence of SARS-CoV-2 variants has raised concerns regarding possible decreases in vaccine effectiveness. Here, neutralizing antibody titers elicited by mRNA-based and adenoviral vector-based vaccines against variant pseudotyped viruses were measured. BNT162b2 and mRNA-1273-elicited antibodies showed modest neutralization resistance against Beta, Delta, Delta plus and Lambda variants whereas Ad26.COV2.S-elicited antibodies from a significant fraction of vaccinated individuals had less neutralizing titer (IC50 <50). The data underscore the importance of surveillance for breakthrough infections that result in severe COVID-19 and suggest a potential benefit by second immunization following Ad26.COV2.S to increase protection from current and future variants.
PMID: 35350781
ISSN: 1664-3224
CID: 5201082

High-titer neutralization of Mu and C.1.2 SARS-CoV-2 variants by vaccine-elicited antibodies of previously infected individuals

Tada, Takuya; Zhou, Hao; Dcosta, Belinda M; Samanovic, Marie I; Cornelius, Amber; Herati, Ramin S; Mulligan, Mark J; Landau, Nathaniel R
Recently identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants Mu and C.1.2 have spike proteins with mutations that may confer resistance to natural and vaccine-elicited antibodies. Analysis of neutralizing antibody titers in the sera of vaccinated individuals without previous history of infection and from convalescent individuals show partial resistance of the viruses. In contrast, sera from individuals with a previous history of SARS-CoV-2 infection who were subsequently vaccinated neutralize variants with titers 4- to 11-fold higher, providing a rationale for vaccination of individuals with previous infection. The heavily mutated C.1.2 spike is the most antibody neutralization-resistant spike to date; however, the avidity of C.1.2 spike protein for angiotensin-converting enzyme 2 (ACE2) is low. This finding suggests that the virus evolved to escape the humoral response but has a decrease in fitness, suggesting that it may cause milder disease or be less transmissible. It may be difficult for the spike protein to evolve to escape neutralizing antibodies while maintaining high affinity for ACE2.
PMCID:8687746
PMID: 34982967
ISSN: 2211-1247
CID: 5107032