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Steps in the right direction HIV-1 mutates rapidly, making it difficult to design a vaccine that will protect people against all of the virus' iterations. A potential successful vaccine design might protect by eliciting broadly neutralizing antibodies (bNAbs), which target specific regions on HIV-1's trimeric envelope glycoprotein (Env) (see the Perspective by Mascola). Jardine et al. used mice engineered to express germline-reverted heavy chains of a particular bNAb and immunized them with an Env-based immunogen designed to bind to precursors of that bNAb. Sanders et al. compared rabbits and monkeys immunized with Env trimers that adopt a nativelike conformation. In both cases, immunized animals produced antibodies that shared similarities with bNAbs. Boosting these animals with other immunogens may drive these antibodies to further mutate into the longsought bNAbs. Chen et al. report that retaining the cytoplasmic domain of Env proteins may be important to attract bNAbs. Removing the cytoplasmic domain may distract the immune response and instead generate antibodies that target epitopes on Env that would not lead to protection. Science , this issue p. 139 , 10.1126/science.aac4223 , p. 156 ; see also p. 191

A major goal for HIV-1 vaccine development is the production of an immunogen to mimic native, functional HIV-1 envelope trimeric spikes (Env) on the virion surface. We lack a reliable description of a native, functional trimer, however, because of inherent instability and heterogeneity in most preparations. We describe here two conformationally homogeneous Envs derived from difficult-to-neutralize primary isolates. All their non-neutralizing epitopes are fully concealed and independent of their proteolytic processing. Most broadly neutralizing antibodies (bnAbs) recognize these native trimers. Truncation of their cytoplasmic tail has little effect on membrane fusion, but it diminishes binding to trimer-specific bnAbs while exposing non-neutralizing epitopes. These results yield a more accurate antigenic picture than hitherto possible of a genuinely untriggered and functional HIV-1 Env; they can guide effective vaccine development.

Less than 200 years after the introduction of the smallpox vaccine, variola virus (VARV) was successfully eradicated by use of vaccines produced with vaccinia virus (VACV) [1]. However, along with the dramatic success of the vaccination program, frequent and sometimes severe adverse reactions to VACV vaccine were encountered, particularly in subjects with immunologic defects or dermatopathologic conditions. Since eradication, VACV vaccine has been reserved for highly selected individuals at risk for orthopoxvirus infections, but there are ongoing concerns over the potential use of VARV as a biological weapon. The development of safer, yet effective vaccines for future use against smallpox therefore remains of considerable interest. Modified vaccinia Ankara (MVA), an attenuated strain of VACV [2, 3], is much less reactogenic than widely used vaccinia strains, such as Dryvax or Elstree [4–8]. MVA was administered to approximately 120 000 persons [9] but was never used in a VARV-endemic area, and its effectiveness at preventing clinical smallpox is unknown. MVA is severely host restricted, and it is either unable to replicate in mammalian cell lines or replicates at a very low level [3, 10, 11]. Approximately 15% of the MVA genome was deleted during in vitro passage, compared with the parental strain [10, 12], but the block in replication in nonpermissive mammalian cells occurs late in the viral life cycle. Thus, because MVA-infected cells express very high levels of virally encoded proteins [13–15], including those encoded by foreign transgenes, there is considerable interest in using MVA as a vector in vaccines to prevent human immunodeficiency virus (HIV) infection, malaria, and infectious diseases due to other pathogens [16–18]. There is also substantial interest in the use of MVA as a vector to deliver tumor-specific antigens to induce immune responses that may help control malignancies, and several of these therapeutic vaccines have advanced to clinical trials [18–20]. Because preliminary studies suggested MVA was safe in immunocompromised hosts [21–24], we hypothesized that MVA would be safe, well-tolerated, and immunogenic in an important, well-characterized immunocompromised population—recipients of a hematopoietic stem cell transplant (HSCT). Vaccination with either traditional calf lymph–derived VACV (such as Dryvax or Elstree) or modern tissue culture-grown strains (the recently approved ACAM2000) are contraindicated for HSCT recipients [25]. Thus, establishing safety and immunogenicity of MVA in this group has implications for pre-event smallpox vaccine contingency planning, as well as for potential therapeutic vaccines against malignancies. We therefore conducted a randomized, placebo-controlled, double-blind study of MVA-BN (IMVAMUNE; Bavarian Nordic A/S, Kvistgaard, Denmark) in 24 individuals who received a HSCT >2 years previously.

Background. We report the first-in-human safety and immunogenicity assessment of a prototype Ad26 vector-based human immunodeficiency virus (HIV) vaccine in humans. Methods. Sixty Ad26-seronegative, healthy, HIV-uninfected subjects were enrolled in a randomized, double-blinded, placebo-controlled, dose-escalation phase 1 study. Five groups of 12 subjects received 109–1011 vp of the Ad26-EnvA vaccine (N = 10/group) or placebo (N = 2/group) at weeks 0 and 24 or weeks 0, 4, and 24. Safety and immunogenicity were assessed. Results. Self-limited reactogenicity was observed after the initial immunization at the highest (1011 vp) dose. No product-related SAEs were observed. All subjects who received the Ad26-EnvA vaccine developed Ad26 NAb titers, EnvA-specific enzyme-linked immunosorbent assays (ELISA) titers, and EnvA-specific enzyme-linked immunospot assays (ELISPOT) responses. These responses persisted at week 52. At week 28 in the 109, 1010, 1011 vp 3-dose and the 1010 and 5 × 1010 vp 2-dose groups, geometric mean EnvA ELISA titers were 6113, 12 470, 8545, 3470, and 9655 and mean EnvA ELISPOT responses were 397, 178, 736, 196, and 1311 SFC/106 peripheral blood mononuclear cells, respectively. Conclusion. This Ad26 vectored vaccine was generally safe and immunogenic at all doses tested. Reactogenicity was minimal with doses of 5 × 1010 vp or less. Ad26 is a promising new vaccine vector for HIV-1. Clinical Trials Registration. {"type":"clinical-trial","attrs":{"text":"NCT00618605","term_id":"NCT00618605"}}NCT00618605.