Immunogenicity and safety of primary fractional-dose yellow fever vaccine in autoimmune rheumatic diseases

Adriana Coracini Tonacio, Tatiana do Nascimento Pedrosa, Eduardo Ferreira Borba, Nadia Emi Aikawa, Sandra Gofinet Pasoto, Júlio Cesar Rente Ferreira Filho, Marília Mantovani Sampaio Barros, Elaine Pires Leon, Suzete Cleusa Ferreira Spina Lombardi, Alfredo Mendrone Junior, Adriana de Souza Azevedo, Waleska Dias Schwarcz, Ricardo Fuller, Emily Figueiredo Neves Yuki, Michelle Remião Ugolini Lopes, Rosa Maria Rodrigues Pereira, Percival Degrava Sampaio Barros, Danieli Castro Oliveira de Andrade, Ana Cristina de Medeiros-Ribeiro, Julio Cesar Bertacini de Moraes, Samuel Katsuyuki Shinjo, Renata Miossi, Alberto José da Silva Duarte, Marta Heloisa Lopes, Esper Georges Kallás, Clovis Artur Almeida da Silva, Eloisa Bonfá, Adriana Coracini Tonacio, Tatiana do Nascimento Pedrosa, Eduardo Ferreira Borba, Nadia Emi Aikawa, Sandra Gofinet Pasoto, Júlio Cesar Rente Ferreira Filho, Marília Mantovani Sampaio Barros, Elaine Pires Leon, Suzete Cleusa Ferreira Spina Lombardi, Alfredo Mendrone Junior, Adriana de Souza Azevedo, Waleska Dias Schwarcz, Ricardo Fuller, Emily Figueiredo Neves Yuki, Michelle Remião Ugolini Lopes, Rosa Maria Rodrigues Pereira, Percival Degrava Sampaio Barros, Danieli Castro Oliveira de Andrade, Ana Cristina de Medeiros-Ribeiro, Julio Cesar Bertacini de Moraes, Samuel Katsuyuki Shinjo, Renata Miossi, Alberto José da Silva Duarte, Marta Heloisa Lopes, Esper Georges Kallás, Clovis Artur Almeida da Silva, Eloisa Bonfá

Abstract

Background: Brazil faced a yellow fever(YF) outbreak in 2016-2018 and vaccination was considered for autoimmune rheumatic disease patients(ARD) with low immunosuppression due to YF high mortality.

Objective: This study aimed to evaluate, prospectively for the first time, the short-term immunogenicity of the fractional YF vaccine(YFV) immunization in ARD patients with low immunossupression.

Methods and results: A total of 318 participants(159 ARD and 159 age- and sex-matched healthy controls) were vaccinated with the fractional-dose(one fifth) of 17DD-YFV. All subjects were evaluated at entry(D0), D5, D10, and D30 post-vaccination for clinical/laboratory and disease activity parameters for ARD patients. Post-vaccination seroconversion rate(83.7%vs.96.6%, p = 0.0006) and geometric mean titers(GMT) of neutralizing antibodies[1143.7 (95%CI 1012.3-1292.2) vs.731 (95%CI 593.6-900.2), p<0.001] were significantly lower in ARD compared to controls. A lower positivity rate of viremia was also identified for ARD patients compared to controls at D5 (53%vs.70%, p = 0.005) and the levels persisted in D10 for patients and reduced for controls(51%vs.19%, p = 0.0001). The viremia was the only variable associated with seroconvertion. No serious adverse events were reported. ARD disease activity parameters remained stable at D30(p>0.05).

Conclusion: Fractional-dose 17DD-YF vaccine in ARD patients resulted in a high rate of seroconversion rate(>80%) but lower than controls, with a longer but less intense viremia. This vaccine was immunogenic, safe and did not induce flares in ARD under low immunosuppression and may be indicated in YF outbreak situations and for patients who live or travel to endemic areas.

Trial registration: This clinical trial was registered with Clinicaltrials.gov (#NCT03430388).

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Study flow diagram.
Fig 1. Study flow diagram.
Fig 2. Yellow fever vaccine (YFV) viremia…
Fig 2. Yellow fever vaccine (YFV) viremia after fractional-dose administration (2A and 2B) in ARD patients and healthy controls (HC).
Peak of viremia in seroconverted (SC+) and non-seroconverted (SC-) ARD patients and healthy controls(HC) (2C).
Fig 3
Fig 3
Longitudinal neutrophils(3A) and lymphocytes(3B) kinetics of ARD patients and healthy controls (HC) after fractional-dose YFV.Values (cell/mm3) represent the mean ± SD of measures for each tiime-point: day 0 or baseline (D0), day 5 (D5), day 10 (D10), and day 30 (D30). The n for ARD patients per day is D0 (n = 159), D5 (n = 148), D10 (n = 147), and D30 (n = 149) and for controls is D0 (n = 159), D5 (n = 158), D10 (n = 156), and D30 (n = 149). *p < 0.05 and ***p < 0.001 compared to day 0 (D0).
Fig 4
Fig 4
Longitudinal neutrophils(4A) and lymphocytes(4B) kinetics in ARD patients vaccinated for YF, comparing neutropenic vs. non-neutropenic and lymphopenic vs. non-lymphopenic patients. Values (cell/mm3) represent the mean ± SD of measures for each time-point: day 0 or baseline (D0), day 5 (D5), day 10 (D10), and day 30 (D30). *p < 0.05, ** < 0.01 and ***p < 0.001 compared to day 0 (D0).

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