The world's first community-based efficacy trial to test an HIV prime-boost vaccine regimen was conducted in 16,402 healthy Thai volunteers, providing the largest safety and reactogenicity data set on a prime-boost regimen with ALVAC-HIV and AIDSVAX B/E. Although the vaccine products (ALVAC-HIV alone or in prime-boost regimens) had been previously evaluated in different populations, the safety data from this study are similar to previous observations in Phase I/II and III studies conducted in Thailand and elsewhere 
. These safety data may be summarized as follows: most of vaccine recipients experienced either local or systemic reactions significantly more frequently than placebo recipients; the frequency of local reactions such as pain and tenderness were higher than that of systemic reactions such as headache, fatigue, arthralgia and myalgia, although fever was rarely reported; ALVAC-HIV is more reactogenic than AIDSVAX B/E; the frequency of the reactions gradually declined with subsequent vaccine administrations; all local and systemic reactogenicity symptoms were mild to moderate in nature, resolving rapidly and spontaneously in the vast majority of cases.
Routine biochemistry and hematologic laboratory values were not assessed in RV144 based on the safety profile observed in previous Phase I and II studies. No differences in any parameter of renal function, hematologic abnormalities, or alterations in CD4 T-cell count were noted among recipients of ALVAC-HIV alone, recipients of ALVAC-HIV with a subunit vaccine, or recipients of control 
The number of cases identified as AEs fall into the usual broad categories that were previously described in phase I/II studies. The frequency of AEs was not significantly different between vaccine and placebo groups. Most AEs occurred after the 30-day post-vaccination period, 3.2% of AEs and none of SAEs being attributed to vaccine. Female participants experienced a higher frequency of AEs and SAEs in both vaccine and placebo groups. The reasons for this difference are unclear. In other studies, male participants experienced less pain than female participants following ALVAC-HIV administration 
. Although a fair comparison cannot be established with Phase I/II trials of the same vaccination regimen, their duration of follow-up being considerably shorter, these observations are in agreement with previous reports that there are few AEs and no SAE related to the administration of this vaccine. In the AIDSVAX B/E phase III trial conducted in 2546 injecting drug users (mostly male) in Bangkok, the proportion of SAEs reported (414, 16.2%) did not differ between vaccine and placebo groups and was similar to the 14.6% reported in this study 
Although ALVAC-HIV is not a vaccinia-derived vaccine, none of the vaccinated individuals presented post vaccination symptoms suggestive of myopericarditis events as described after smallpox vaccination 
None of the 160 deaths reported in this trial were assessed as related to the candidate vaccines and were mostly related to trauma and cardiovascular causes. The number of Sudden Unexplained Death Syndrome (SUDS) events (n
5) is less than the expected case number (8.4) calculated from the number of person years (32,300 male person years) and the published rate estimate in 20–49 year old men from northeastern Thailand (25.9/100,000 person years) 
. In a previous AIDSVAX B/E efficacy trial conducted in 2527 injecting drug user participants in Bangkok, 102 deaths were reported with no difference between vaccine and placebo recipients and none being attributed to vaccine 
. A similar observation was made on phase I/II trials of ALVAC alone or ALVAC and subunit prime-boost regimens with 7 deaths out of 1497 participants, none related to vaccination 
Overall, the prime-boost regimen did not result in more abnormal pregnancy outcomes in vaccine than in placebo female recipients. This corroborates previous findings in phase I/II and III trials 
. In Thailand, the induced abortion ratio has been estimated at 19.5 for 1000 live births 
contrasting with the 4.9% reported in this study. In this study, the proportion of induced abortions documented must be interpreted with caution, as induced abortion is illegal in Thailand and most pregnancy outcome data are derived from the volunteer's report. The spontaneous abortion rate of 9.1% is closer to the estimated rate of 6.9% formerly reported from a Thai hospital 
. Although not statistically significant, the higher number of abortions (spontaneous and induced) among vaccine recipients merits close scrutiny in future trials of ALVAC and protein combinations.
Small clinical trials with either recombinant canarypox or envelope subunit vaccines did not reveal safety issues in newborns and infants from HIV-infected mothers 
. Moreover, gp120 envelope subunit was shown to be safe in HIV-infected pregnant women 
. In several studies, ALVAC-HIV (vCP1452) has been safely administered to immuno-compromised HIV-infected subjects 
. ALVAC recombinants have been administered to humans and animals by parenteral and oral routes without signs of replication, systemic dissemination or severe reaction. In principle, it should be impossible for canarypox recombinants to disseminate in the environment, as the recombinants would not be synthesized in mammalian cells as complete virus. ALVAC is an attenuated canarypox virus and is non-pathogenic in its host species, other birds, mammals and humans. It may be infectious for birds, though there are already five canarypox-based veterinary vaccines 
The results of the ALVAC-HIV and AIDSVAX B/E prime-boost regimen confirm that the regimen is safe and well tolerated among a large population of healthy HIV-uninfected adults in Thailand. Although occurrence of local and systemic reactions was reported among the vaccinated participants, very few adverse events were related to the vaccine products. No death was attributed to the vaccination regimen. Altogether, these findings indicate that ALVAC-HIV and AIDSVAX B/E are safe and well tolerated and may be suitable for further study and large-scale public use, should efficacy be judged adequate to have a public health impact.