The Yellow Fever (YF) vaccine (17D or 17DD strains) is widely used, with almost 100 million doses distributed annually worldwide.1 It is one of the most effective vaccines ever made 2 and the key to eliminating YF epidemics.3 Tropical regions of Africa and Central and South America are endemic to YF, and people living in or traveling to those regions should be vaccinated.4 In Brazil, since 2017, in response to a YF outbreak outside the endemic Amazon region, vaccination became recommended nationwide for individuals aged nine months up to 59-years with no contra-indications to the vaccine.5

As a live attenuated viral vaccine, the YF vaccine is contraindicated for individuals with conditions that increase the risk for a serious adverse event, including elders, people with history of thymectomy and people with immunocompromising disorders, such as People Living With HIV (PLWH) with severe immunodeficiency (CD4 < 200 cells/µL or < 15 % in children below 6-years).6

YF vaccine-related serious adverse events are rare and include hypersensitivity reactions, neurological disease (encephalitis, meningitis, autoimmune diseases involving the central and peripheral nervous system, described as YF vaccine Associated Neurologic Disease [YEL-AND]) and viscerotropic disease (generalized multisystem infection, similar to severe forms of the disease, described as YF vaccine Associated Viscerotropic Disease [YEL-AVD]). In Brazil, passive surveillance estimated the incidence of serious adverse events as 0.3 cases per 100,000 administered doses from 2000 to 2015.7

In PLWH, safety data on YF vaccine are limited to observational studies (mostly retrospective) and few recent prospective studies.8-12 Although a case of fatal YEL-AND was reported in a 53-year-old man with undiagnosed HIV infection and a CD4 of 108 cells/µL,13 most studies that included PLWH have reported reassuring results on the safety profile of the YF vaccine in PLWH with CD4 ≥350 cells/µL. The majority of adverse events observed were mild and self-limited, including injection site reactions, nausea, myalgia, fever and laboratorial abnormalities (i.e., neutropenia, lymphopenia, thrombocytopenia, AST and ALT elevations).8,11

The mechanisms leading to YF vaccine serious adverse events remain unclear, with individual host's and vaccine's characteristics probably involved.14 After vaccination, 17D/17DD viruses replicate in the lymphoid and reticuloendothelial tissues.15 This viremia occurs early and is similar to the natural infection's incubation period.16 Some studies found that replication can last longer after vaccination, particularly among elders.17,18 Noteworthy, the causality definition for YEL-AVD requires viral detection in blood or tissues.19

We showed recently that the 17DD vaccine was safe and well tolerated in PLWH.20 However, we found that 17DD viremia was associated with adverse events in PLWH and HIV-uninfected controls (HIV(-) controls).20 In this study, we aimed to further explore factors associated with the occurrence of 17DD viremia in PLWH and HIV(-) controls. In addition, we describe the kinetics of hematological and liver laboratorial parameters and assess whether 17DD viremia and HIV status were associated with the occurrence of laboratorial abnormalities.

This longitudinal study provides further evidence on YF (17DD) primo-vaccination safety in PLWH with CD4 ≥200 cells/µL. Through an extensive evaluation of post-vaccination 17DD viremia and hematological and liver laboratorial parameters kinetics, we found that PLWH experienced 17DD viremia twice more frequently than HIV(-) controls. Moreover, we observed benign and transient decreases in neutrophils, lymphocytes and platelets at Day 5 after 17DD vaccination. 17DD viremia was independently associated with lower lymphocyte and platelet levels at Day 5. Finally, we did not observe ALT elevations after 17DD vaccination.

We found that 17DD viremia was twice more frequent among PLWH than in HIV(-) controls (23% vs. 12 %). Our results differ from previous prospective studies that have reported a much higher frequency of 17DD/17D viremia (but not different between PLWH and their control groups). In a study from Brazil, 17DD viremia occurred in 40 % of PLWH and 34 % of the controls (defined as at least one detectable result measured by quantitative rt-PCR in plasma samples collected at Days 3, 5, 7 and 14 after vaccination).11 In France, 17D viremia was found in 82 % of PLWH and 77 % of the controls (quantitative rt-PCR in plasma samples collected at Day 7).8 Differences regarding vaccines used (17DD in Brazil and 17D in France), intervals between vaccination and samples collection, and the characteristics of the employed assays may explain the varying 17DD/17D viremia frequencies across the studies. Moreover, the high baseline prevalence of DENV IgG antibodies (83 %) found in our study may provide additional insights. Heterologous immunity, characterized by cross-reactivity and cross-protection from other flaviviruses’ previous infections (i.e., DENV, Japanese encephalitis virus and ZKV), may result in lower 17DD viremia.26,27 In a 17DD dose-response study from Brazil, 17DD viremia (measured by PFU) was less frequent in participants with DENV antibodies.28 Similarly, in our study 17DD viremia was less frequent among participants with DENV IgG antibodies (18% vs. 31 %). Nonetheless, the association between DENV IgG antibodies and 17DD viremia was non-significant in the adjusted regression models. Importantly, though we have found that HIV status was associated with the occurrence of 17DD viremia, there was no clear association between specific HIV biomarkers (i.e., baseline CD4, CD4/CD8 ratio and HIV-RNA) and the odds of 17DD viremia. These negative findings may be due to a lower number of participants with low CD4, low CD4/CD8 ratio and high HIV-RNA included.

We observed significant decreases in neutrophils at Day 5 after 17DD vaccination. Baseline neutrophil levels were the major factor associated with Day 5 levels although a non-significant linear association of lower baseline CD4 and lower neutrophil at Day 5 was observed. Previous studies suggested that neutrophil levels fall up to 10 days after vaccination and recover one month after vaccination, suggesting that neutrophil nadir values observed at Day 5 could be even lower if measured at Day 10.29-31 In PLWH, in which lower levels of neutrophils were not uncommon,32 neutropenia could be aggravated following 17DD vaccination.

The kinetics of lymphocytes observed in our study was similar between PLWH and HIV(-) controls. 17DD viremia was independently associated with lower lymphocyte counts at Day 5, which could be potentially explained by a more enhanced acute immune response among 17DD viremic participants, leading to homing of peripheric lymphocytes to lymphoid tissues.33,34 Early and transient drop of lymphoid cells, natural killer cells, and lymphocytes T and B, has been described following 17D/17DD vaccination in healthy adults.34,35 In a subanalysis of our main study, we further described a significant drop in lymphocytes T CD4+ at Day 5, in both PLWH and controls, returning to baseline levels at Day 30.36 Decrease of CD4+ T lymphocytes and relative increase of CD8+ T lymphocytes had been documented following 17D/17DD vaccination.8,35,37

Minor decreases in platelet counts were observed at Day 5 and were associated with lower baseline platelet levels and with the occurrence of 17DD viremia. Flaviviruses infections often result in a decrease in the platelet count as result of direct viruses toxicity, immunological platelet destruction, megakaryocytes (cells responsible for platelets production in the bone marrow) destruction and impaired megakaryopoiesis.38 Early and transient drop in platelet levels following 17D/17DD vaccine has been reported in healthy adults and PLWH.8,11 Finally, minimal liver laboratorial abnormalities were found in this study. ALT levels did not increase post-vaccination and were not associated with 17DD viremia or HIV infection status.

Our results should be interpreted with caution. This study included mostly PLWH with high baseline CD4 and undetectable HIV-RNA, underpowering the analyses to detect significant effects of advanced HIV infection on 17DD viremia and laboratorial abnormalities following 17DD vaccination. Nevertheless, our study has strengths that should be highlighted. To our knowledge, this study has included and prospectively followed the largest sample of PLWH exposed to 17DD primo vaccination, providing critical data on YF vaccine safety in PLWH and a detailed panel of safety laboratorial kinetics. Moreover, to avoid potential confounding of non-primo vaccination (since they are less likely to present with post-vaccination adverse events), we have restricted the study population to participants without serological evidence of prior YF vaccination/disease. Finally, we have also explored the potential effect of heterologous immunity from previous flaviviruses infections (i.e., DENV and ZKV antibodies) on 17DD viremia.

The YF vaccine 17DD was safe in PLWH with CD4 ≥200 cells/µL. Post-vaccination 17DD viremia was twice higher in PLWH than in HIV(-) controls. Transient and self-limited decreases in lymphocytes, neutrophils and platelets were observed. 17DD viremia occurrence was associated with lower lymphocytes and platelets nadir after vaccination. YF vaccination of individuals oblivious of their HIV infection should not pose additional risk (assuming those with CD4 < 200 cells/µL would be less likely to have undisclosed HIV infection). Altogether, the results from this study support the current recommendation and the safety of YF vaccine in PLWH with CD4 ≥200 cells/µL.

This work was funded by National Council for Scientific and Technological Development – CNPq and Presidência da Fundação Oswaldo Cruz/ Vice-presidência de Pesquisa e Coleções Biológicas VPPCB/Fiocruz – Chamada CNPq/Fiocruz n 16/2017– PROEP/PEC (# 420674/2017-9). This work was also supported by Instituto Nacional de Infectologia Evandro Chagas (INI/Fiocruz) and Coordenação de Vigilância em Saúde e Laboratórios de Referência(CVSLR)/FIOCRUZ/ MS. B.G. acknowledges funding from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ).