Conference Highlights — Development Volume 17 Issue 2 April/May 2009

HIV Vaccine Development

David I. Watkins, PhD

Several interesting new vaccine-related studies were presented at the 16th to the HLA-A*02-bound Nef Conference on Retroviruses and Opportunistic this year. Transmitted LV10. The vaccinees who showed a re- viruses appear to be derived from cell-free virus rather than cell-associated sponse to this epitope before virus, at least in men who have sex with men. Follow-up studies from the Step did better than those that did not. (HIV Vaccine Trials Network 502) trial indicated that if individuals mounted Further evidence for the concept certain vaccine-induced responses, they may control viral replication after that CD8+ T-cell recognition of good infection. Finally, adeno-associated-virus-derived neutralizing results in control of viral rep- completely protected macaques from infection, suggesting novel mechanisms lication was presented by Streeck and of viral control. colleagues (Abstract 112). The authors showed that if individuals recognized frequently targeted immunodominant Transmission trial (HIV Vaccine Trials Network 502 epitopes during the acute infection study) (Abstract 119). It was suggested phase, they would control viral replica- One of the highlights of the 2008 that despite relatively robust vaccine- tion later. Preservation of this recogni- (15th) Conference on Retroviruses induced T-cell responses, the breadth tion pattern into the chronic infection and Opportunistic Infections was the of these responses may not have been phase also correlated with a slower discovery that only a few HIV variants sufficient to protect against HIV infec- CD4+ decline. cross the mucosa to initiate viral infec- tion or reduce postinfection viral loads Finally, 2 studies (Abstracts 90aLB, tion. At the 2009 (16th) conference in the majority of vaccinees. New T- 90bLB) presented the effects of inter- this year, data were presented suggest- cell vaccine approaches may, there- leukin-2 on clinical outcomes. Despite ing that the origin of the infecting virus fore, have to be qualitatively different evidence of preservation of CD4+ cells in semen is cell-free virus rather than or include an component in and increases in some patients, there viral DNA present in cells (Abstract the future. was no reduction in the rate of oppor- 49LB). Four transmission pairs of men In an attempt to explain why vac- tunistic infections or death. who have sex with men (MSM) were cinees in the Step trial with high ad- studied; sequences of the virus pres- enovirus serotype 5 (Ad5) neutralizing Monkey Vaccine Studies ent in plasma of the infected recipi- antibodies were more susceptible to ent clustered with donor cell-free virus Using Attenuated Simian HIV infection, the immune response to Immunodeficiency Virus from semen rather than viral DNA in Ad5 was monitored in individuals par- lymphocytes from semen. It will now ticipating in phase I studies (Abstract Two studies (Abstracts 116, 117) shed be important to assess the origin of 85). Approximately 73% of individuals light on protection induced by live at- the transmitted virus in heterosexual already had Ad-specific T cells before tenuated simian immunodeficiency vi- transmission pairs and in men in- receiving the vaccine. Only individu- rus (SIV) SIVmac239∆Nef. The first study ex- fected by genital secretions. Nonethe- als given 3 injections of 3 × 1010 viral amined the expansion of natural killer less, this result suggests that particles showed a statistically signifi- (NK) cells (CD3-, CD8+, NKG2A+) after should target cell-free virus rather than cant increase in the percentage of Ad- and challenge. NK cells ex- cell-associated virus. Furthermore, the specific CD4+ and CD8+ T cells. These panded by as much as 8-fold in 70% of cell-free viral challenges employed in CD4+, Ad5-specific cells exhibited mac- the vaccinated animals. Similarly, NK macaque challenge studies may be rel- rophage inhibitory protein (MIP)-1 alpha expansion was observed in challenged evant to HIV transmission. activity, which the authors speculated vaccinated monkeys, in the absence of might make them resistant to HIV in- obvious anamnestic responses, imply- Step Trial Follow-Up fection. ing that these NK cells may play a role In a follow-up study of the Step trial, in vaccine-induced protection. In a symposium on “Learning from data suggest that if vaccinees show a The second monkey study involving Negative Trials,” Hunter discussed pos- response to a “good” epitope after vac- SIVmac239∆Nef showed that depletion of sible reasons for the failure of the Step cination, they will likely exert some B cells had little effect on vaccine-in- measure of control over viral replica- duced protection. Although not all of tion after infection (Abstract 86LB). the vaccinated macaques exhibited Dr Watkins is a Professor in the Department Although this would be expected for adequate B-cell depletion, 5 of 10 anti- of Pathology and a member of the AIDS epitopes bound by the “protective” al- CD20-antibody-treated animals had no Vaccine Research Laboratory at the Univer- leles HLA-B*57 and -B*27, there were SIV-specific antibody at time of challenge. sity of Wisconsin Madison. 9 individuals who showed a response Of these, 4 of 5 showed no evidence of

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replication of the challenge virus, and uals with subsequent cloning of the im- replication can be controlled by T cells the other showed only limited viral munoglobulin heavy and light chains. alone, in the absence of -specific replication and subsequent control. After transfection of these heavy and antibody responses. Thus, B-cell responses likely play only a light chains, it was possible to produce marginal role in vaccine protection in- neutralizing antibodies. New HIV Vaccine Testing duced by SIVmac239∆Nef. One of the most interesting and novel discoveries reported at this year’s Finally, encouraging immune respons- Vaccine Development conference involved the use of adeno- es were engendered in a safety trial of a associated virus as a gene therapy protein vaccine adjuvanted (with AS01) In a symposium titled “Vaccines—Back agent to express an SIV-specific neutral- and consisting of a recombinant fusion to Basics,” several elegant antibody izing monoclonal antibody (Abstract protein containing p17, p24 Gag, re- studies were described. The first pre- 164). Three monkeys treated in this verse transcriptase, and Nef (Abstract

sented an analysis looking at the first way resisted challenge with SIVmac316, 87LB). Additionally, there were no vac- antibodies present after detection of whereas 6 naive macaques became cine-related serious adverse effects. At virus (Abstract 162). At 8 days postin- infected and developed sustained viral the highest doses of this vaccine, 80% fection, antibody-virion complexes were replication out to 12 months postin- of the human volunteers showed rec- present, followed by antibody to fection. This novel approach may well ognition of all 4 antigens in the vac- at 13 days. Anti-gp120-specific antibod- hold substantial promise as a method cine, with a mean CD4+ cell reactivity ies appeared at 28 days post-viral de- of controlling the HIV epidemic. of 1.2%. Interestingly, few CD8+ T-cell tection. Mathematical modeling sug- Encouraging news from the T-cell responses were seen in the vaccinees. gested that these antibodies had little vaccine field closed this symposium Further human testing is planned for effect on reducing acute-phase viremia (Abstract 165). Vaccination with a this vaccine approach. given the timing of their appearance DNA/Ad5 regimen encoding all of the Financial Disclosure: Dr Watkins has re- during natural infection. SIV proteins except Env induced high- ceived an honorarium for a lecture to scien- Mascola discussed approaches to frequency and broad T-cell responses tists at Pfizer Inc. generate broadly reactive neutralizing in 8 macaques. Repeated low-dose antibodies (brNAbs) (Abstract 163). mucosal challenge with a heterologous A list of all cited abstracts ap- These antibodies may be more com- virus demonstrated that these vaccine- pears on pages 89-95. mon than previously thought, and new induced T-cell responses controlled methods for developing additional replication of the challenge virus in 6 brNAbs were described. This involved of 8 vaccinees. These data suggest that Top HIV Med. 2009;17(2):35-36 sorting of B cells from infected individ- both acute- and chronic-phase viral ©2009, International AIDS Society–USA

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