4. Discussion 4.1. Analysis of Results
Immunogenicity in trials was analyzed by fold increase of Geometric Mean Titer from baseline to post dose 3( Figure 6). The fold increase of all antibody titers in patients injected with CYD-TDV vaccine is larger when compared to control groups in all trials. For example, in HSS et al 21, the antibody titer against DENV3 increased 12.37 fold in test group and only 1.03 in control group. This trend is seen across all trials for antibodies against all 4 antigens. This indicates that the CYD-TDV is more effective in eliciting a protective immune response against the four dengue virus serotypes.
Another trend common to test groups in all trials is that the antibody titers reached high levels after dose 2, but the subsequent dose( dose 3) failed to increase it further substantially. This presents as a plateau-shaped pattern in Figures 2-5. In HSS et al, 21 the GMT for DENV 1 antibody increased from 15.3 at baseline, to 119.0 post dose 2, which is an increase of 114.3. However, at the end of dose 3, the GMT only reached 151.0, which is a meagre increase of 32.0 from post dose 2. This trend is consistent in all trials, as seen in Figures 2-5.
This plateau pattern implies that 2 doses of CYD-TDV vaccine are more immunogenic, hence more effective, than the third dose. However, the three dose regimen is still supported. Observations from some trials 21, 22, 24 stated that the third dose significantly increased GMT levels in patients who were flavivirus seronegative at baseline, but not in patients who were flavivirus-seropositive at baseline. This means that the third dose is still effective for previously flavivirus seronegative patients. Moreover, in a clinical setting, it is impractical to assess antigen seropositivity before vaccine administration. Therefore, it is still most efficient to standardize a three dose regimen for this vaccination.
Finally, we also observed that the magnitude of immune response in test groups is different between trials, as some trials show more robust immune responses than others. We can compare the strength of immune responses in each study by comparing the peak antibody titers( GMT) recorded( Figure 7). In all 4 serologies, the highest and second highest peaks were achieved by Dayan, et al. 20 and Villar, et al.
24 respectively.
A possible explanation for this is that the populations in these studies had high baseline DENV seropositivities( Table 2). High baseline seropositivity rates imply that a large portion of the population selected in these trials have had previous exposure to dengue virus. The baseline seropositivity in the test group of Dayan et, al. 20 and Villar et, al 24 was 69 % and 75.1 % respectively. This is much higher than the values reported by Leo et al( 16.6 %), 25 HSS, et al 21( 44.9 %), and Lanata, et al. 22( 37.2 %), all of whom had a relatively low peak antibody titer for all serologies. In previously seropositive patients, the dengue vaccine would elicit a secondary, instead of a primary, immune response. This explains the more enhanced peak GMT levels found in Dayan, et al. 20 and Villar, et al.
From the safety and reactogenicity reports in all trials( Table 9), CYD-TDV vaccine is well tolerated and has a relatively good safety profile. As reported, all solicited injection-site or systemic adverse effects were similar in both test and control groups in all trials. Systemic and injection-site adverse effects were generally described as low grade in all trials. Unsolicited systemic adverse reactions occurred in similar rates between test and control groups in all studies, but were generally described to be unrelated to the injections.
The safety profile of the tested CYD-TDV is similar to that of other vaccines commonly used. The study by Villar, et al. 24 used DPT as the injection in control group( Table 2). From Table 9, we see that in this study, the rate of incidence of adverse effects is similar in test and control groups, which implies that the safety profile of the CYD-TDV is similar to that of the DPT vaccine. The control groups of studies by Lanata, et al. 22 and Leo, et al. 25 also used alternative vaccines. Hence, the similarities in the data for reactogenicity in control and test groups of these studies also implies a similar safety profile between the CYD-TDV and the vaccine they used for their control group.
Severe adverse effects were reported in all trials. However, they occurred in similar rates between control and test groups. The incidence of severe adverse effects is not unexpected as the trials lasted for