CASSIA GISELE TERRASSANI SILVEIRA
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
3 resultados
Resultados de Busca
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- Ontogeny of the B- and T-cell response in a primary Zika virus infection of a dengue-naive individual during the 2016 outbreak in Miami, FL(2017) RICCIARDI, Michael J.; MAGNANI, Diogo M.; GRIFONI, Alba; KWON, Young-Chan; GUTMAN, Martin J.; GRUBAUGH, Nathan D.; GANGAVARAPU, Karthik; SHARKEY, Mark; SILVEIRA, Cassia G. T.; BAILEY, Varian K.; PEDRENO-LOPEZ, Nuria; GONZALEZ-NIETO, Lucas; MAXWELL, Helen S.; DOMINGUES, Aline; MARTINS, Mauricio A.; PHAM, John; WEISKOPF, Daniela; ALTMAN, John; KALLAS, Esper G.; ANDERSEN, Kristian G.; STEVENSON, Mario; LICHTENBERGER, Paola; CHOE, Hyeryun; WHITEHEAD, Stephen S.; SETTE, Alessandro; WATKINS, David I.Zika virus (ZIKV) is a mosquito-borne flavivirus of significant public health concern. In the summer of 2016, ZIKV was first detected in the contiguous United States. Here we present one of the first cases of a locally acquired ZIKV infection in a dengue-naive individual. We collected blood from a female with a maculopapular rash at day (D) 5 and D7 post onset of symptoms (POS) and we continued weekly blood draws out to D148 POS. To establish the ontogeny of the immune response against ZIKV, lymphocytes and plasma were analyzed in a longitudinal fashion. The plasmablast response peaked at D7 POS (19.6% of CD19(+) B-cells) and was undetectable by D15 POS. ZIKV-specific IgM was present at D5 POS, peaked between D15 and D21 POS, and subsequently decreased. The ZIKV-specific IgG response, however, was not detected until D15 POS and continued to increase after that. Interestingly, even though the patient had never been infected with dengue virus (DENV), cross-reactive IgM and IgG binding against each of the four DENV serotypes could be detected. The highest plasma neutralization activity against ZIKV peaked between D15 and D21 POS, and even though DENV binding antibodies were present in the plasma of the patient, there was neither neutralization nor antibody dependent enhancement (ADE) of DENV. Interestingly, ADE against ZIKV arose at D48 POS and continued until the end of the study. CD4(+) and CD8(+) T-cells recognized ZIKV-NS2A and ZIKV-E, respectively. The tetramer positive CD8(+) T-cell response peaked at D21 POS with elevated levels persisting for months. In summary, this is the first study to establish the timing of the ontogeny of the immune response against ZIKV.
- Dengue Virus Evades AAV-Mediated Neutralizing Antibody Prophylaxis in Rhesus Monkeys(2017) MAGNANI, Diogo M.; RICCIARDI, Michael J.; BAILEY, Varian K.; GUTMAN, Martin J.; PEDRENO-LOPEZ, Nuria; SILVEIRA, Cassia G. T.; MAXWELL, Helen S.; DOMINGUES, Aline; GONZALEZ-NIETO, Lucas; SU, Qin; NEWMAN, Ruchi M.; PACK, Melissa; MARTINS, Mauricio A.; MARTINEZ-NAVIO, Jose M.; FUCHS, Sebastian P.; RAKASZ, Eva G.; ALLEN, Todd M.; WHITEHEAD, Stephen S.; BURTON, Dennis R.; GAO, Guangping; DESROSIERS, Ronald C.; KALLAS, Esper G.; WATKINS, David I.Development of vaccines against mosquito-borne Flaviviruses is complicated by the occurrence of antibody-dependent enhancement (ADE), which can increase disease severity. Long-term delivery of neutralizing antibodies (nAbs) has the potential to effectively block infection and represents an alternative to vaccination. The risk of ADE may be avoided by using prophylactic nAbs harboring amino acid mutations L234A and L235A (LALA) in the immunoglobulin G (IgG) constant region. Here, we used recombinant adeno-associated viruses (rAAVs) to deliver the anti-dengue virus 3 (DENV3) nAb P3D05. While the administration of rAAV-P3D05-rhesus immunoglobulin GI (rhIgGl)-LALA to rhesus macaques engendered DENV3-neutralizing activity in serum, it did not prevent infection. The emergence of viremia following DENV3 challenge was delayed by 3-6 days in the rAAV-treated group, and replicating virus contained the envelope mutation K64R. This neutralization-resistant variant was also confirmed by virus outgrowth experiments in vitro. By delivering P3D05 with unmutated Fc sequences, we further demonstrated that DENV3 also evaded wild-type nAb prophylaxis, and serum viral loads appeared to be higher in the presence of low levels of unmutated P3D05-rhIgGl. Our study shows that a vectored approach for long-term delivery of nAbs with the LALA mutations is promising, but prophylaxis using a single nAb is likely insufficient at preventing DENV infection and replication.
- Potent Plasmablast-Derived Antibodies Elicited by the National Institutes of Health Dengue Vaccine(2017) MAGNANI, Diogo M.; SILVEIRA, Cassia G. T.; RICCIARDI, Michael J.; GONZALEZ-NIETO, Lucas; PEDRENO-LOPEZ, Nuria; BAILEY, Varian K.; GUTMAN, Martin J.; MAXWELL, Helen S.; DOMINGUES, Aline; COSTA, Priscilla R.; FERRARI, Lilian; GOULART, Raphaella; MARTINS, Mauricio A.; MARTINEZ-NAVIO, Jose M.; FUCHS, Sebastian P.; KALIL, Jorge; TIMENETSKY, Maria do Carmo; WRAMMERT, Jens; WHITEHEAD, Stephen S.; BURTON, Dennis R.; DESROSIERS, Ronald C.; KALLAS, Esper G.; WATKINS, David I.Exposure to dengue virus (DENV) is thought to elicit lifelong immunity, mediated by DENV-neutralizing antibodies (nAbs). However, Abs generated by primary infections confer serotype-specific protection, and immunity against other serotypes develops only after subsequent infections. Accordingly, the induction of these nAb responses acquired after serial DENV infections has been a long-sought-after goal for vaccination. Nonetheless, it is still unclear if tetravalent vaccines can elicit or recall nAbs. In this study, we have characterized the responses from a volunteer who had been previously exposed to DENV and was immunized with the live attenuated tetravalent vaccine Butantan-DV, developed by the NIH and Butantan Institute. Eleven days after vaccination, we observed an similar to 70-fold expansion of the plasmablast population. We generated 21 monoclonal Abs (MAbs) from singly sorted plasmablasts. These MAbs were the result of clonal expansions and had significant levels of somatic hypermutation (SHM). Nineteen MAbs (90.5%) neutralized at least one DENV serotype at concentrations of 1 mu g/ml or less; 6 of the 21 MAbs neutralized three or more serotypes. Despite the tetravalent composition of the vaccine, we observed a neutralization bias in the induced repertoire: DENV3 was targeted by 18 of the 19 neutralizing MAbs (nMAbs). Furthermore, the P3D05 nMAb neutralized DENV3 with extraordinary potency (concentration to achieve half-maximal neutralization [Neut(50)] = 0.03 mu g/ml). Thus, the Butantan-DV vaccine engendered a mature, antigen-selected B cell repertoire. Our results suggest that preexisting responses elicited by a previous DENV3 infection were recalled by immunization. IMPORTANCE The dengue epidemic presents a global public health challenge that causes widespread economic burden and remains largely unchecked by existing control strategies. Successful control of the dengue epidemic will require effective prophylactic and therapeutic interventions. Several vaccine clinical efficacy trials are approaching completion, and the chances that one or more live attenuated tetravalent vaccines (LATVs) will be introduced worldwide is higher than ever. While it is widely accepted that dengue virus (DENV)-neutralizing antibody (nAb) titers are associated with protection, the Ab repertoire induced by LATVs remain uncharacterized. Here, we describe the isolation of potent (Neut(50) < 0.1 mu g/ml) nAbs from a DENV-seropositive volunteer immunized with the tetravalent vaccine Butantan-DV, which is currently in phase III trials.