The results of this study showed that expedited high dose HBV vaccination series with GM-CSF as an adjuvant did not improve development of HBsAb titers. The data confirm previous findings that GM-CSF is safe and well tolerated in HIV-infected individuals, albeit with some transient, anticipated side effects. However, co-administration of GM-CSF with HBV vaccine failed to improve HBsAb titer. In fact, the observed response rate was somewhat higher in the vaccine only arm as compared to the GM-CSF arm (65% vs. 52%, not statistically significant), yielding an overall response rate of 59% at 4 weeks after completion of the vaccination series. Unfortunately, the proportion of responders waned to 40% by week 60, suggesting that the response was not durable.
GM-CSF failed to serve as an effective adjuvant to HBV vaccination in this study. This is somewhat surprising given previously published data in patients with end stage renal disease and in HIV-infected patients. A four-dose regimen of HBV vaccine with either GM-CSF (3 mcg/kg) or placebo with the first injection in unvaccinated end stage renal disease subjects yielded positive results [15
]. One month after completion of the vaccination series, 44% of subjects in the placebo arm versus 100% in the GM-CSF arm developed protective immunity (P<0.02). A subsequent study evaluating the efficacy of GM-CSF as an adjuvant in subjects on long term dialysis who were non-responders to 40 mcg recombinant HBV vaccination given at an accelerated schedule showed similar benefit. They received one additional dose of HBV vaccine and were randomized to receive either 300 mcg GM-CSF (n=12) or placebo (n=7) [16
]. In that study, 92% in the GM-CSF arm versus 0% in the placebo arm responded with a protective HBsAb titer (p=0.001). As noted in the Sasaki trial of HIV-infected subjects, there was a trend toward improved protective immunity among those who received GM-CSF one month after completing the vaccine series, but the durability of vaccine responses was not assessed [26
]. While those results suggested promise for the role of GM-CSF to augment immune response to vaccination in HIV-infected persons, our results failed to confirm their findings. Given that we used a much higher dose than in the Sasaki study, there may be a threshold dose of GM-CSF above which response is mitigated [27
]. However, the studies in ESRD patients illustrated efficacy with even higher doses of GM-CSF [15
Use of higher dose HBV vaccine (40 mcg dose) was selected in this study based on ACIP recommendations and previous research illustrating that this approach offers better responses among HIV-infected persons [26
]. Fonseca et al randomized 210 HIV-infected persons to standard (20 mcg dose) vs. double dose (40 mcg dose) and reported a better seroconversion with the higher dose (47 vs. 34%, p=0.07). This improvement was most noticeable for those with CD4+ T-cell counts ≥350 c/mm3
(64 vs. 39%) and HIV viral loads <10,000 cp/mL (58 vs. 37%). However, another trial comparing 10 mcg vs. 40 mcg dosing of HBV vaccine reported no differences in seroconversion rates between the two strategies (61% and 62%, respectively) [32
]. Still, more subjects who received the 40 mcg dose developed HBsAb titers >100 mIU/mL. Sasaki et al. reported a seroconversion rate of 66% in 80 HIV-infected age 18–35 years with CD4+ T-count >350 c/mm3
who received the 40 mcg dose of vaccine. Our results are similar to these reports and confirm that the higher dose of HBV vaccine yields better seroconversion rates than reports from retrospective cohorts [10
]. Baseline CD4+ T cells and HIV viral load were not found to be statistically significant in our evaluation of protective immunity, but our study was not powered to assess predictive factors. Nonetheless, age was statistically significant in its association with protective immunity at week 16.
We also elected to give HBV vaccine on an expedited schedule (0, 4, and 12 weeks) rather than (0, 4, and 60 weeks). Additional studies in other immunocompromised patient populations have shown that an accelerated schedule yields improved results. Rosman et al. administered an accelerated and high dose of vaccine to a cohort of 100 alcoholic patients [33
]. The high-dose and accelerated regimen group responded at a higher rate than the standard vaccine schedule patients (75% versus 46%, p<0.005) with the mean HBsAb titer higher in the accelerated group (76.4 versus 39.6 mIU/mL, p<0.01). Similar results were reported in a study of a high-dose (40 mcg), modified schedule vaccination regimen (0, 1, and 2 months with a booster dose at 6 months) in a study performed in HIV-infected persons [34
]. In their study, 89% of the subjects developed protective antibody with 60% developing an HBsAb >1000mIU/mL, and response to vaccine was strongly correlated with controlled viremia. Another study subsequent to ours was recently presented that assessed an accelerated (0,1 and 3 weeks) versus a standard (0,4, and 24 weeks)schedule among 1330 HIV-infected subjects [35
]. Completion rate of the three dose series was higher with the accelerated schedule (92% vs. 83%), but development of a protective response with the accelerated schedule was similar to standard schedule only for persons with high CD4 cell counts (>500 c/mm3). Several additional studies illustrate that the conventional vaccine series is difficult to complete. In a recent large study from the military with highly regimented health care, only 62% of 626 HIV-infected persons received 3 doses of HBV vaccine [36
]. Given this data, we elected to use an expedited vaccine schedule of 0, 4, and 12 weeks. While this generated a 59% overall response rate at week 16, only 40% of vaccinees had durable protection 1 year after vaccination. Additional research is needed to determine the optimal schedule to generate a protective immune response.
Our trial was subject to limitations of small-scale studies. The study size limited our ability to determine the factors associated with the development of a protective immune response (notably CD4+ T-cell count and plasma HIV RNA). Longer follow up would also provide more information regarding durability, but the decline in subjects with protective antibody at 60 weeks suggests that an additional booster dose of vaccine may be required to maintain protective antibodies. And while our study aimed to optimize response in all subjects by using high dose vaccine and an expedited schedule, it is not possible to distinguish the two effects in the overall response rate. Specifically, the use of an accelerated schedule may have mitigated the benefit reported in previous trials with GM-CSF. Nonetheless, there was no evidence that addition of GM-CSF improves response in this setting. Finally, the durability of the response may have been affected negatively by the accelerated schedule.
However, our study suggests that the vaccine responses to the strategies utilized in this study still fall short of the responses in HIV-uninfected individuals. While the use of adjuvants offers the potential to boost immune response, we failed to find a significant effect from GM-CSF in this study. Given the shared routes of transmission for HIV and HBV, there remains an urgent need for research to further explore the underlying mechanism limiting immune responses to this vaccine and to develop better strategies to induce protective immunity.