Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish.

Xenograft cell transplantation into immunodeficient mice has become the gold standard for assessing pre-clinical efficacy of cancer drugs, yet direct visualization of single-cell phenotypes is difficult. Here, we report an optically-clear prkdc-/-, il2rga-/- zebrafish that lacks adaptive and natural killer immune cells, can engraft a wide array of human cancers at 37°C, and permits the dynamic visualization of single engrafted cells. For example, photoconversion cell-lineage tracing identified migratory and proliferative cell states in human rhabdomyosarcoma, a pediatric cancer of muscle. Additional experiments identified the preclinical efficacy of combination olaparib PARP inhibitor and temozolomide DNA-damaging agent as an effective therapy for rhabdomyosarcoma and visualized therapeutic responses using a four-color FUCCI cell-cycle fluorescent reporter. These experiments identified that combination treatment arrested rhabdomyosarcoma cells in the G2 cell cycle prior to induction of apoptosis. Finally, patient-derived xenografts could be engrafted into our model, opening new avenues for developing personalized therapeutic approaches in the future.

Immunization for HIV-1 Broadly Neutralizing Antibodies in Human Ig Knockin Mice.

A subset of individuals infected with HIV-1 develops broadly neutralizing antibodies (bNAbs) that can prevent infection, but it has not yet been possible to elicit these antibodies by immunization. To systematically explore how immunization might be tailored to produce them, we generated mice expressing the predicted germline or mature heavy chains of a potent bNAb to the CD4 binding site (CD4bs) on the HIV-1 envelope glycoprotein (Env). Immunogens specifically designed to activate B cells bearing germline antibodies are required to initiate immune responses, but they do not elicit bNAbs. In contrast, native-like Env trimers fail to activate B cells expressing germline antibodies but elicit bNAbs by selecting for a restricted group of light chains bearing specific somatic mutations that enhance neutralizing activity. The data suggest that vaccination to elicit anti-HIV-1 antibodies will require immunization with a succession of related immunogens.

Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes.

The envelope glycoprotein trimer mediates HIV-1 entry into cells. The trimer is flexible, fluctuating between closed and more open conformations and sometimes sampling the fully open, CD4-bound form. We hypothesized that conformational flexibility and transient exposure of non-neutralizing, immunodominant epitopes could hinder the induction of broadly neutralizing antibodies (bNAbs). We therefore modified soluble Env trimers to stabilize their closed, ground states. The trimer variants were indeed stabilized in the closed conformation, with a reduced ability to undergo receptor-induced conformational changes and a decreased exposure of non-neutralizing V3-directed antibody epitopes. In rabbits, the stabilized trimers induced similar autologous Tier-1B or Tier-2 NAb titers to those elicited by the corresponding wild-type trimers but lower levels of V3-directed Tier-1A NAbs. Stabilized, closed trimers might therefore be useful components of vaccines aimed at inducing bNAbs.

Structural evolution of glycan recognition by a family of potent HIV antibodies.

The HIV envelope glycoprotein (Env) is densely covered with self-glycans that should help shield it from recognition by the human immune system. Here, we examine how a particularly potent family of broadly neutralizing antibodies (Abs) has evolved common and distinct structural features to counter the glycan shield and interact with both glycan and protein components of HIV Env. The inferred germline antibody already harbors potential binding pockets for a glycan and a short protein segment. Affinity maturation then leads to divergent evolutionary branches that either focus on a single glycan and protein segment (e.g., Ab PGT124) or engage multiple glycans (e.g., Abs PGT121-123). Furthermore, other surrounding glycans are avoided by selecting an appropriate initial antibody shape that prevents steric hindrance. Such molecular recognition lessons are important for engineering proteins that can recognize or accommodate glycans.

Progesterone inactivation in decidual stromal cells: A mechanism for inflammation-induced parturition.

The process of human parturition involves inflammation at the interface where fetal chorion trophoblast cells interact with maternal decidual stromal (DS) cells and maternal immune cells in the decidua (endometrium of pregnancy). This study tested the hypothesis that inflammation at the chorion-decidua interface (CDI) induces labor by negating the capacity for progesterone (P4) to block labor and that this is mediated by inactivation of P4 in DS cells by aldo-keto reductase family 1 member C1 (AKR1C1). In human, Rhesus macaque, and mouse CDI, AKR1C1 expression increased in association with term and preterm labor. In a human DS cell line and in explant cultures of term human fetal membranes containing the CDI, the prolabor inflammatory cytokine, interleukin-1ß (IL-1ß), and media conditioned by LPS-stimulated macrophages increased AKR1C1 expression and coordinately reduced nuclear P4 levels and P4 responsiveness. Loss of P4 responsiveness was overcome by inhibition of AKR1C1 activity, inhibition of AKR1C1 expression, and bypassing AKR1C1 activity with a P4 analog that is not metabolized by AKR1C1. Increased P4 activity in response to AKR1C1 inhibition was prevented by the P4 receptor antagonist RU486. Pharmacologic inhibition of AKR1C1 activity prevented parturition in a mouse model of inflammation-induced preterm parturition. The data suggest that inflammatory stimuli at the CDI drive labor by inducing AKR1C1-mediated P4 inactivation in DS cells and that inhibiting and/or bypassing of AKR1C1-mediated P4 inactivation is a plausible therapeutic strategy to mitigate the risk of inflammation-associated preterm birth.

The harms of promoting the lab leak hypothesis for SARS-CoV-2 origins without evidence.

Science is humanity's best insurance against threats from nature, but it is a fragile enterprise that must be nourished and protected. The preponderance of scientific evidence indicates a natural origin for SARS-CoV-2. Yet, the theory that SARS-CoV-2 was engineered in and escaped from a lab dominates media attention, even in the absence of strong evidence. We discuss how the resulting anti-science movement puts the research community, scientific research, and pandemic preparedness at risk.

Glycan heterogeneity as a cause of the persistent fraction in HIV-1 neutralization.

Neutralizing antibodies (NAbs) to multiple epitopes on the HIV-1-envelope glycoprotein (Env) have been isolated from infected persons. The potency of NAbs is measured more often than the size of the persistent fraction of infectivity at maximum neutralization, which may also influence preventive efficacy of active or passive immunization and the therapeutic outcome of the latter. Many NAbs neutralize HIV-1 CZA97.012, a clone of a Clade-C isolate, to ~100%. But here NAb PGT151, directed to a fusion-peptide epitope, left a persistent fraction of 15%. NAb PGT145, ligating the Env-trimer apex, left no detectable persistent fraction. The divergence in persistent fractions was further analyzed by depletion of pseudoviral populations of the most PGT151- and PGT145-reactive virions. Thereby, neutralization by the non-depleting NAb increased, whereas neutralization by the depleting NAb decreased. Furthermore, depletion by PGT151 increased sensitivity to autologous neutralization by sera from rabbits immunized with soluble native-like CZA97.012 trimer: substantial persistent fractions were reduced. NAbs in these sera target epitopes comprising residue D411 at the V4-ß19 transition in a defect of the glycan shield on CZA97.012 Env. NAb binding to affinity-fractionated soluble native-like CZA97.012 trimer differed commensurately with neutralization in analyses by ELISA and surface plasmon resonance. Glycan differences between PGT151- and PGT145-purified trimer fractions were then demonstrated by mass spectrometry, providing one explanation for the differential antigenicity. These differences were interpreted in relation to a new structure at 3.4-Å resolution of the soluble CZA97.012 trimer determined by cryo-electron microscopy. The trimer adopted a closed conformation, refuting apex opening as the cause of reduced PGT145 binding to the PGT151-purified form. The evidence suggests that differences in binding and neutralization after trimer purification or pseudovirus depletion with PGT145 or PGT151 are caused by variation in glycosylation, and that some glycan variants affect antigenicity through direct effects on antibody contacts, whereas others act allosterically.

Affinity Maturation of a Potent Family of HIV Antibodies Is Primarily Focused on Accommodating or Avoiding Glycans.

The high-mannose patch on the HIV-1 envelope (Env) glycoprotein is the epicenter for binding of the potent broadly neutralizing PGT121 family of antibodies, but strategies for generating such antibodies by vaccination have not been defined. We generated structures of inferred antibody intermediates by X-ray crystallography and electron microscopy to elucidate the molecular events that occurred during evolution of this family. Binding analyses revealed that affinity maturation was primarily focused on avoiding, accommodating, or binding the N137 glycan. The overall antibody approach angle to Env was defined very early in the maturation process, yet some variation evolved in the PGT121 family branches that led to differences in glycan specificities in their respective epitopes. Furthermore, we determined a crystal structure of the recombinant BG505 SOSIP.664 HIV-1 trimer with a PGT121 family member at 3.0 Å that, in concert with these antibody intermediate structures, provides insights to advance design of HIV vaccine candidates.

Transfer Printing of Ordered Plasmonic Nanoparticles at Hard and Soft Interfaces with Increased Fidelity and Biocompatibility Supports a Surface Lattice Resonance.

Transfer printing, the relocation of structures assembled on one surface to a different substrate by adjusting adhesive forces at the surface-substrate interface, is widely used to print electronic circuits on biological substrates like human skin and plant leaves. The fidelity of original structures must be preserved to maintain the functionality of transfer-printed circuits. This work developed new biocompatible methods to transfer a nanoscale square lattice of plasmon resonant nanoparticles from a lithographed surface onto leaf and glass substrates. The fidelity of the ordered nanoparticles was preserved across a large area in order to yield, for the first time, an optical surface lattice resonance on glass substrates. To effect the transfer, interfacial adhesion was adjusted by using laser induction of plasmons or unmounted adhesive. Optical and confocal laser scanning microscopy showed that submicron spacing of the square lattice was preserved in ≥90% of transfer-printed areas up to 4 mm2. Up to 90% of ordered nanoparticles were transferred, yielding a surface lattice resonance measured by transmission UV-vis spectroscopy.

Outcomes reported in randomised trials of surgical prehabilitation: a scoping review.

BACKGROUND: Heterogeneity of reported outcomes can impact the certainty of evidence for prehabilitation. The objective of this scoping review was to systematically map outcomes and assessment tools used in trials of surgical prehabilitation. METHODS: MEDLINE, EMBASE, PsychInfo, Web of Science, CINAHL, and Cochrane were searched in February 2023. Randomised controlled trials of unimodal or multimodal prehabilitation interventions (nutrition, exercise, psychological support) lasting at least 7 days in adults undergoing elective surgery were included. Reported outcomes were classified according to the International Society for Pharmacoeconomics and Outcomes Research framework. RESULTS: We included 76 trials, mostly focused on abdominal or orthopaedic surgeries. A total of 50 different outcomes were identified, measured using 184 outcome assessment tools. Observer-reported outcomes were collected in 86% of trials (n=65), with hospital length of stay being most common. Performance outcomes were reported in 80% of trials (n=61), most commonly as exercise capacity assessed by cardiopulmonary exercise testing. Clinician-reported outcomes were included in 78% (n=59) of trials and most frequently included postoperative complications with Clavien-Dindo classification. Patient-reported outcomes were reported in 76% (n=58) of trials, with health-related quality of life using the 36- or 12-Item Short Form Survey being most prevalent. Biomarker outcomes were reported in 16% of trials (n=12) most commonly using inflammatory markers assessed with C-reactive protein. CONCLUSIONS: There is substantial heterogeneity in the reporting of outcomes and assessment tools across surgical prehabilitation trials. Identification of meaningful outcomes, and agreement on appropriate assessment tools, could inform the development of a prehabilitation core outcomes set to harmonise outcome reporting and facilitate meta-analyses.

Towards a common definition of surgical prehabilitation: a scoping review of randomised trials.

BACKGROUND: There is no universally accepted definition for surgical prehabilitation. The objectives of this scoping review were to (1) identify how surgical prehabilitation is defined across randomised controlled trials and (2) propose a common definition. METHODS: The final search was conducted in February 2023 using MEDLINE, Embase, PsycINFO, Web of Science, CINAHL, and Cochrane. We included randomised controlled trials (RCTs) of unimodal or multimodal prehabilitation interventions (nutrition, exercise, and psychological support) lasting at least 7 days in adults undergoing elective surgery. Qualitative data were analysed using summative content analysis. RESULTS: We identified 76 prehabilitation trials of patients undergoing abdominal (n=26, 34%), orthopaedic (n=20, 26%), thoracic (n=14, 18%), cardiac (n=7, 9%), spinal (n=4, 5%), and other (n=5, 7%) surgeries. Surgical prehabilitation was explicitly defined in more than half of these RCTs (n=42, 55%). Our findings consolidated the following definition: 'Prehabilitation is a process from diagnosis to surgery, consisting of one or more preoperative interventions of exercise, nutrition, psychological strategies and respiratory training, that aims to enhance functional capacity and physiological reserve to allow patients to withstand surgical stressors, improve postoperative outcomes, and facilitate recovery.' CONCLUSIONS: A common definition is the first step towards standardisation, which is needed to guide future high-quality research and advance the field of prehabilitation. The proposed definition should be further evaluated by international stakeholders to ensure that it is comprehensive and globally accepted.

International consensus is needed on a core outcome set to advance the evidence of best practice in cancer prehabilitation services and research.

Prehabilitation aims to optimise patients' physical and psychological status before treatment. The types of outcomes measured to assess the impact of prehabilitation interventions vary across clinical research and service evaluation, limiting the ability to compare between studies and services and to pool data. An international workshop involving academic and clinical experts in cancer prehabilitation was convened in May 2022 at Sheffield Hallam University's Advanced Wellbeing Research Centre, England. The workshop substantiated calls for a core outcome set to advance knowledge and understanding of best practice in cancer prehabilitation and to develop national and international databases to assess outcomes at a population level.

Readability of Patient-Facing Information of Antibiotics Used in the WHO Short 6-Month and 9-Month All Oral Treatment for Drug-Resistant Tuberculosis.

OBJECTIVES: Readability of patient-facing information of oral antibiotics detailed in the WHO all oral short (6 months, 9 months) has not been described to date. The aim of this study was therefore to examine (i) how readable patient-facing TB antibiotic information is compared to readability reference standards and (ii) if there are differences in readability between high-incidence countries versus low-incidence countries. METHODS: Ten antibiotics, including bedaquiline, clofazimine, ethambutol, ethionamide, isoniazid, levofloxacin, linezolid, moxifloxacin, pretomanid, pyrazinamide, were investigated. TB antibiotic information sources were examined, consisting of 85 Patient Information Leaflets (PILs) and 40 antibiotic web resouces. Of these 85 PILs, 72 were taken from the National Medicines Regulator from six countries (3 TB high-incidence [Rwanda, Malaysia, South Africa] + 3 TB low-incidence [UK, Ireland, Malta] countries). Readability data was grouped into three categories, including (i) high TB-incidence countries (n = 33 information sources), (ii) low TB-incidence countries (n = 39 information sources) and (iii) web information (n = 53). Readability was calculated using Readable software, to obtain four readability scores [(i) Flesch Reading Ease (FRE), (ii) Flesch-Kincaid Grade Level (FKGL), (iii) Gunning Fog Index and (iv) SMOG Index], as well as two text metrics [words/sentence, syllables/word]. RESULTS: Mean readability scores of patient-facing TB antibiotic information for FRE and FKGL, were 47.4 ± 12.6 (sd) (target ≥ 60) and 9.2 ± 2.0 (target ≤ 8.0), respectively. There was no significant difference in readability between low incidence countries and web resources, but there was significantly poorer readability associated with PILs from high incidence countries versus low incidence countries (FRE; p = 0.0056: FKGL; p = 0.0095). CONCLUSIONS: Readability of TB antibiotic PILs is poor. Improving readability of PILs should be an important objective when preparing patient-facing written materials, thereby improving patient health/treatment literacy.

Australian rheumatologists' perception of autologous haemopoietic stem cell transplantation for the treatment of systemic sclerosis: a cross-sectional survey.

BACKGROUND: Autologous haemopoietic stem cell transplantation (AHSCT) is an effective treatment for systemic sclerosis (SSc); however, treatment-related toxicity remains a key issue. AIMS: To investigate the perceptions of rheumatologists on the use of AHSCT for SSc. METHODS: Australian rheumatologists were asked for their opinion on the role of AHSCT, the indications for treatment and the barriers to the use of AHSCT for SSc. A secondary analysis assessed what factors influenced the perception of AHSCT. RESULTS: A total of 77.8% rheumatologists agreed or strongly agreed with the statement that AHSCT is an accepted treatment for SSc. While 65.1% agreed or strongly agreed that treatment-associated mortality was a significant barrier to referral for AHSCT, only 15.2% agreed or strongly agreed that this risk was unacceptable. Progressive lung or skin disease, or lack of response to other therapies, were considered the main referral criteria. A total of 92.0% of respondents agreed or strongly agreed that reduction of treatment toxicity would increase their likelihood to refer patients for AHSCT. Rheumatologists who were aware of the correct evidence base were more likely to consider AHSCT an acceptable treatment for SSc (4.21 ± 0.7 vs 3.64 ± 0.9, P = 0.007). Rheumatologists desire improved patient selection criteria and access to treatment. CONCLUSION: In this national survey of rheumatologists, AHSCT is considered an accepted therapy. However, concern about toxicity remains a potential barrier to patient referral. Access, studies to refine patient selection and development of AHSCT protocols that improve safety were identified as key areas of need.

Avacopan as an additional therapeutic intervention to promote renal recovery in severe ANCA-associated vasculitis: A case report.

Avacopan, a C5a receptor antagonist (C5aR) presents a new therapeutic option to improve outcomes in ANCA-associated vasculitis (AAV). Here we present a case report of a patient initially requiring kidney replacement therapy (KRT), where avacopan was added as an additional adjunctive therapeutic agent late in the treatment course.

Stage 1 and 2 Palliation: Comparing Ductal Stenting and Aorto-Pulmonary Shunts in Single Ventricles with Duct-Dependent Pulmonary Blood Flow.

Patent ductus arteriosus stenting (PDAS) for ductal-dependent pulmonary blood flow (DDPBF) provides a new paradigm for managing neonates with single ventricles (SV). Currently, sparse data exist regarding outcomes for subsequent palliation. We describe our experience with inter-stage care and stage 2 (S2P) conversion with PDAS in comparison to a prior era of patients who received surgical aorto-pulmonary shunts (APS). Retrospective review of 18 consecutive DDPBF SV patients treated with PDAS between 2016 and 2021 was done and compared with 9 who underwent APS from 2010 to 2016. Patient outcomes and pulmonary artery (PA) growth were analyzed. S2P was completed in all 18 with PDAS with no cardiac arrests and one post-S2P mortality. In the 9 APS patients, there was one cardiac arrest requiring ECMO and one mortality inter-stage. Off cardiopulmonary bypass strategy was utilized in 10/18 in the PDAS and 1/9 in the APS group (p = 0.005) at S2P. Shorter ventilation time, earlier PO feeding, and shorter hospital stay were noted in the PDAS group (p = 0.01, p = 0.006, p = 0.03) (S2P). Median Nakata index increase inter-stage was not significant between the PDAS and APS at 94.1 mm2/m2 versus 71.7 mm2/m2 (p = 0.94). Median change in pulmonary artery symmetry (PAS) was - 0.02 and - 0.24, respectively, which was statistically significant (p = 0.008). Neurodevelopmental outcomes were better in the PDAS group compared to the APS group (p = 0.02). PDAS provides excellent PA growth, inter-stage survival, progression along multistage single-ventricle palliation, and potentially improved neurodevelopmental outcomes. Most patients can be transitioned through 2 stages of palliation without CPB.

Conformational antigenic heterogeneity as a cause of the persistent fraction in HIV-1 neutralization.

BACKGROUND: Neutralizing antibodies (NAbs) protect against HIV-1 acquisition in animal models and show promise in treatment of infection. They act by binding to the viral envelope glycoprotein (Env), thereby blocking its receptor interactions and fusogenic function. The potency of neutralization is largely determined by affinity. Less well explained is the persistent fraction, the plateau of remaining infectivity at the highest antibody concentrations. RESULTS: We observed different persistent fractions for neutralization of pseudovirus derived from two Tier-2 isolates of HIV-1, BG505 (Clade A) and B41 (Clade B): it was pronounced for B41 but not BG505 neutralization by NAb PGT151, directed to the interface between the outer and transmembrane subunits of Env, and negligible for either virus by NAb PGT145 to an apical epitope. Autologous neutralization by poly- and monoclonal NAbs from rabbits immunized with soluble native-like B41 trimer also left substantial persistent fractions. These NAbs largely target a cluster of epitopes lining a hole in the dense glycan shield of Env around residue 289. We partially depleted B41-virion populations by incubating them with PGT145- or PGT151-conjugated beads. Each depletion reduced the sensitivity to the depleting NAb and enhanced it to the other. Autologous neutralization by the rabbit NAbs was decreased for PGT145-depleted and enhanced for PGT151-depleted B41 pseudovirus. Those changes in sensitivity encompassed both potency and the persistent fraction. We then compared soluble native-like BG505 and B41 Env trimers affinity-purified by each of three NAbs: 2G12, PGT145, or PGT151. Surface plasmon resonance showed differences among the fractions in antigenicity, including kinetics and stoichiometry, congruently with the differential neutralization. The large persistent fraction after PGT151 neutralization of B41 was attributable to low stoichiometry, which we explained structurally by clashes that the conformational plasticity of B41 Env causes. CONCLUSION: Distinct antigenic forms even of clonal HIV-1 Env, detectable among soluble native-like trimer molecules, are distributed over virions and may profoundly mold neutralization of certain isolates by certain NAbs. Affinity purifications with some antibodies may yield immunogens that preferentially expose epitopes for broadly active NAbs, shielding less cross-reactive ones. NAbs reactive with multiple conformers will together reduce the persistent fraction after passive and active immunization.

Diversification and expansion of the EBV-reactive cytotoxic T lymphocyte repertoire following autologous haematopoietic stem cell transplant for multiple sclerosis.

Both genetic susceptibility and environmental exposures are thought to be involved in multiple sclerosis (MS) pathogenesis. Of all viruses potentially relevant to MS aetiology, Epstein-Barr virus (EBV) is the best-studied. EBV is a B cell lymphotropic virus which is able to evade the immune system by establishing latent infection in memory B cells, and EBV reactivation is restricted by CD8 cytotoxic T cell (CTL) responses in immune competent individuals. Autologous haematopoietic stem cell transplantation (AHSCT) is considered to be the most effective therapy in the treatment of relapsing MS even though chemotherapy-induced lymphopenia can associate with the re-emergence of latent viruses. Despite the increasing interest in EBV and MS pathogenesis the relationship between AHSCT, EBV and viral immunity in people with MS has not been investigated to date. This study analysed immune responses to EBV in a well characterised cohort of 13 individuals with MS by utilising pre-AHSCT, and 6-, 12- and 24-month post AHSCT bio-banked peripheral blood mononuclear cells and plasma samples. It is demonstrated that the infused stem cell product contains latently EBV-infected memory B cells, and that EBV viremia occurs in the immune-compromised recipient post-transplant. High throughput TCR analysis detected expansion and diversification of the CD8 CTL responses reactive with EBV lytic and latent antigens from 6 to 24 months following AHSCT. Increased levels of latent EBV infection found within the B cell pool following treatment, as measured by EBV genomic detection, did not associate with disease relapse. This is the first study of EBV immunity following application of AHSCT in the treatment of MS and not only raises important questions about the role of EBV infection in MS pathogenesis, but is of clinical importance given the expanding clinical trials of adoptive EBV-specific CTLs in MS.

Reappraising the Value of HIV-1 Vaccine Correlates of Protection Analyses.

With the much-debated exception of the modestly reduced acquisition reported for the RV144 efficacy trial, HIV-1 vaccines have not protected humans against infection, and a vaccine of similar design to that tested in RV144 was not protective in a later trial, HVTN 702. Similar vaccine regimens have also not consistently protected nonhuman primates (NHPs) against viral acquisition. Conversely, experimental vaccines of different designs have protected macaques from viral challenges but then failed to protect humans, while many other HIV-1 vaccine candidates have not protected NHPs. While efficacy varies more in NHPs than humans, vaccines have failed to protect in the most stringent NHP model. Intense investigations have aimed to identify correlates of protection (CoPs), even in the absence of net protection. Unvaccinated animals and humans vary vastly in their susceptibility to infection and in their innate and adaptive responses to the vaccines; hence, merely statistical associations with factors that do not protect are easily found. Systems biological analyses, including artificial intelligence, have identified numerous candidate CoPs but with no clear consistency within or between species. Proposed CoPs sometimes have only tenuous mechanistic connections to immune protection. In contrast, neutralizing antibodies (NAbs) are a central mechanistic CoP for vaccines that succeed against other viruses, including SARS-CoV-2. No HIV-1 vaccine candidate has yet elicited potent and broadly active NAbs in NHPs or humans, but narrow-specificity NAbs against the HIV-1 isolate corresponding to the immunogen do protect against infection by the autologous virus. Here, we analyze why so many HIV-1 vaccines have failed, summarize the outcomes of vaccination in NHPs and humans, and discuss the value and pitfalls of hunting for CoPs other than NAbs. We contrast the failure to find a consistent CoP for HIV-1 vaccines with the identification of NAbs as the principal CoP for SARS-CoV-2.