Integrated immunogenicity analysis of a tetravalent dengue vaccine up to 4 y after vaccination

Abstract

Two large pivotal phase III studies demonstrated the efficacy of the tetravalent dengue vaccine (CYD-TDV; Dengvaxia®, Sanofi Pasteur) against all dengue serotypes. Here we present an unprecedented integrated summary of the immunogenicity of CYD-TDV to identify the parameters driving the neutralizing humoral immune response and evolution over time. We summarized the immunogenicity profiles of a 3-dose schedule of CYD-TDV administered 6 months apart across 10 phase II and 6 phase III trials undertaken in dengue endemic and non-endemic countries. Dengue neutralizing antibody titers in sera were determined at centralized laboratories using the 50% plaque reduction neutralization test (PRNT50) at baseline, 28 d after the third dose, and annually thereafter for up to 4 y after the third dose in some studies. CYD-TDV elicits neutralizing antibody responses against all 4 dengue serotypes; geometric mean titers (GMTs) increased from baseline to post-dose 3. GMTs were influenced by several parameters including age, baseline dengue seropositivity and region. In the 2 pivotal studies, GMTs decreased initially during the first 2 y post-dose 3 but appear to stabilize or slightly increase again in the third year. GMTs persisted 1.2–3.2-fold higher than baseline levels for up to 4 y post-dose 3 in other studies undertaken in dengue endemic countries. Our integrated analysis captures the fullness of the CYD-TDV immunogenicity profile across studies, age groups and regions; by presenting the available data in this way general trends and substantial outliers within each grouping can be easily identified. CYD-TDV elicits neutralizing antibody responses against all dengue serotypes, with differences by age and endemicity, which persist above baseline levels in endemic countries.

Long-term immunogenicity and safety of tetravalent dengue vaccine (CYD-TDV) in healthy populations in Singapore and Vietnam: 4-year follow-up of randomized, controlled, phase II trials

“…In an integrated immunogenicity analysis of ten phase II and six phase III trials that administered CYD-TDV in Asia Pacific and Latin Americaincluding the initial Vietnam and Singapore studiesparticipants who were seropositive to dengue at baseline demonstrated higher GMTs up to four years after the third dose, irrespective of region. 10 The GMTs against all four serotypes at the four-year follow-up were generally lower to those observed at one year post-vaccination in both countries. 6,7 This is in contrast with another four-year immunogenicity and safety follow-up of CYD-TDV in participants aged 2-45 years in the Philippines, a country considered highly endemic for dengue, where GMTs remained similar to those observed at one year post-vaccination.…”

Immunogenicity and safety of a dengue vaccine given as a booster in Singapore: a randomized Phase II, placebo-controlled trial evaluating its effects 5–6 years after completion of the primary series

“…At 28 days after booster injection, participants who were dengue seronegative at baseline had higher relative GMT increases for each serotype than those dengue immune; which may reflect lower pre-booster GMTs in dengue seronegative participants, and thereby allowing for proportionally greater increases in post-booster GMTs. Of note, higher GMTs post-dose 3 have been observed in other countries, particularly in endemic regions, 13 whereas Singapore (CYD28) may be generally considered a country with lower endemicity, despite resurgence in recent years. 8 Consideration should also be made for the recent results from Sridhar et al, which used a dengue anti-non-structural protein 1 (NS1) IgG enzyme-linked immunosorbent assay to retrospectively assess the impact of inferred baseline dengue serostatus on safety outcomes following vaccination with CYD-TDV.…”

“…In CYD28, dengue seropositivity among participants at baseline was 32.4% for those in the control group and 26.5% in the vaccine group; 12 figures reflecting Singapore's lower endemicity compared with other Southeast Asian and Latin American countries, and the South East Asian region in general. 13 The CYD28 study showed an overall favorable safety profile for CYD-TDV, increased seropositivity rates, and increased neutralizing antibody titers against all four dengue virus serotypes, post-dose 3. 12 Whether a booster dose may be required in certain populations with low dengue endemicity, such as Singapore, remains to be elucidated.…”

When Can One Vaccinate with a Live Vaccine after Wild-Type Dengue Infection?

“…While prior infection history will have to be documented through viral diagnostic or serological assays such as Rapid Diagnostic Tests before vaccination, it is of course not intended to assess the level and specificity of individual neutralizing responses through quantitative assays such as PRNT 50 . One can however, based on clinical evidence across a large number of studies [36], propose that after the refractory period, pre-existing responses would in majority enhance vaccine immunogenicity. Figure 3 illustrates and summarizes the points developed above, addressing the introduction of a multidose vaccine in presence of infection-induced immune responses, and Table 1 summarizes the nature and potential role/impact of innate and adaptive responses induced by wild type dengue infection regarding subsequent live vaccination.…”

“…Similarly, co-administration of YF17D and CYD-TDV did not result in negative interferences at the serological level [41,42]. A larger study looked at the impact of prior YF or JE immunity on CYD dengue-induced antibody responses [36]. This study was conducted across ten phase II and six phase III trials undertaken with the CYD dengue vaccine in endemic and non-endemic countries.…”