Safety concerns for the use of these vectors in humans will represent a significant challenge to clinical development. Broadly neutralizing antibody Immunogens that elicit bNAb remain a high priority. ideas and a sustained long-term commitment of scientists, governments, and the community. viral inhibition [46-48], or other immune functions such non-neutralizing antibody avidity  and antibody-dependent cytotoxicity and antibody-dependent cell-mediated viral inhibition [50,51] may provide a more robust indication of functional antiviral activity. A particular consideration should be given to the exploration of the vaccine-induced mucosal responses, since 48740 RP a study of ALVAC-SIV with a low-dose, repetitive SIV challenge delivered in milk showed protection of neonatal macaques in the absence of detectable IFN- ELISPOT responses; conversely, MVA-SIV did not protect against this challenge despite generating IFN- ELISPOT responses . In the absence of a defined correlate of protection, it will be difficult to screen candidates for future clinical development without efficacy testing in phase IIb trials. Several questions arise: 1) can pre-defined immune selection criteria to rank vaccine approaches be applied generally (whatever 48740 RP the approach), within vector platform classes (pox viruses) only, or within insert classes (mosaics, conserved sequences); 2) is usually more, better, if we do not know what more means or should we assume that, like the tide, higher general immune responses will improve the unknown specific response desired? Animal models Post Step, work was focused on high-dose intravenous pathogenic SIV challenge since the MRKAd5 HIV-1 vaccine did not have an effect on SIV acquisition or viral load in this challenge model  corroborating the Step findings . The modest success of the ALVAC-HIV and AIDSVAX? gp120 B/E prime-boost regimen has focused greater attention on low-dose mucosal challenges in NHP. Recent work suggests that protection against homologous and heterologous contamination Rabbit polyclonal to VDAC1 acquisition is possible, and unlike high dose intravenous challenge, protection against low-dose challenge is not necessarily associated with viral load control in breakthrough infections (Franchini G; 48740 RP Nabel G, Letvin N, personal communication). Despite criticism of the SHIV challenge model since the Step study  the development of pathogenic SHIVs that can be used in low-dose challenge settings may be an important part of the development of NHP models that will inform Env subunit design and selection . Induction of broad cell-mediated responses The Step and RV144 results reinforce the need to develop new vaccines able to induce stronger, broader and more sustained humoral and CMI responses, in particular at the mucosal level [54*]. Heterologous vectors and inserts If a vaccine can induce greater breadth of T- and B-cell responses to HIV than occurs naturally during acute infection, then the use of a combination of protective epitopes in a preventive vaccine may control the early dissemination of HIV, resulting in a lower viral set 48740 RP point and better long-term immune control . A heterologous regimen with adenovirus primary and poxvirus boost offers promising leads [56-58]. Regimens heterologous for their antigens may broaden the CMI responses against conserved epitopes [59,60,61*,62] as suggested by a regimen with DNA and MVA vaccines heterologous for their inserts inducing strong T-cell responses . Other pox vectors such as MVA and NYVAC in heterologous prime-boost regimens with DNA or vector primary and with or without subunit boost may be tested in future efficacy studies [17,21,64]. Polyvalent mosaic antigens are designed to optimize cellular immunologic coverage of global HIV-1 sequence diversity. Mosaic HIV antigens expressed by Ad26 vectors markedly augmented both the breadth and depth of antigen-specific CMI responses as compared with consensus or natural sequence HIV antigens in rhesus monkeys. Polyvalent mosaic and conserved sequence antigens therefore represent promising strategies to expand.