December 1, 2022, is the 35th "World AIDS Day". Many places across the country have announced the latest AIDS prevention and treatment situation. The published content shows that the scale of HIV infection is still growing, the total number of infected people is increasing, and it is becoming more common among young students and the elderly. It has to be admitted that AIDS is still an important public health issue around the world. AIDS, the full name of acquired immunodeficiency syndrome (AIDS), is a progressive immune deficiency characterized by a decrease in human CD4+T lymphocytes caused by human infection with human immunodeficiency virus (HIV). In the later stages of the disease, various opportunistic infections, malignant tumors and central nervous system lesions can be secondary to the comprehensive disease. This disease is harmful and has a high mortality rate.
Figure 1 Research focus on AIDS treatment
Although existing blocking drugs can effectively block infection during the window period of , they have been helpless about infection after the window period. Scientists have also been hoping to develop an efficient vaccine that can truly prevent AIDS. However, this vaccine must be able to induce a wide range of neutralizing antibodies (bnAbs) to identify various different HIV strains that have mutated, in order to prevent HIV infection. However, inducing bnAbs through vaccination has so far been elusive. A key challenge is that bnAbs themselves rarely occur, even during infection, and bnAb precursors are not commonly found in the human immune system.
In light of this, The team of Adrian B. McDermott from the National Institutes of Health's Vaccine Research Center designed vaccines specifically targeted at recruiting these rare bnAb precursors, developing an approach known as "germline targeting" that has driven major advances in immunology and is broadly applicable to HIV as well as other pathogens. The study also conducted a proof-of-concept through clinical trials and found that the potential HIV vaccine eOD-GT860mer (with AS01B as adjuvant) had a good safety profile and induced inflammatory response in 97% of vaccine recipients. VRC01 class bnAb precursors, the median frequency of immunoglobulin GB cells in the blood reaches 0.1%, these bnAb precursors have the same properties as bnAbs and have acquired somatic hypermutation and affinity through enhancement. The research content was published in the top international journal "Science" on December 2, 2022, under the title "Vaccination induces HIV broadly neutralizing antibody precursors in humans", and was highlighted in Science.
[HIV vaccine design strategy triggering bnAbs]
bnAbs, like all antibodies, are produced by B cells. When B cells mature from their original germline state, they acquire affinity-enhancing mutations. Previously, researchers have found that most HIV The Env protein has no detectable affinity for bnAb germline precursors, which greatly affects the design and development of HIV vaccine strategies, as it suggests that a specific immunogen with bnAb germline precursor affinity is required to elicit a bnAb response, and that a different booster immune original is required to select for antibody maturation to produce bnAbs. guides the immune response through the maturation stage using sequential vaccination of different antigens . The HIV vaccine field is currently pursuing three strategies to elicit bnAbs: (i) B-cell lineage vaccine design, in which a series of immunogens are derived from a series of Env variants isolated from longitudinal analysis of bnAb development in naturally HIV-1 infected individuals; (ii) Germline-targeted vaccine designs, where the priming immunogen is designed to bind multiple precursors within the bnAb class (spanning many lineages), enhancing the immunogens in turn to more closely resemble native Env trimers; (iii) epitope focused vaccine designs, where a series of immunogens are designed to focus responses to one or more specific structural epitopes on the trimer . In each of the above strategies, the initiation phase is the most critical, because if B cell precursors with the potential to develop into bnAbs are not stimulated in time, the rest of the subsequent vaccine may fail. In response to these strategies, Experimental Medicine (Phase 1) clinical trials are currently being conducted or planned to test priming immunogens or sequential combinations of immunogens to explore whether they can elicit the desired antibody response .
Figure 2 Frequency of antigen-specific and epitope-specific B cells.
[First human trial of targeted strategy]
In this study, it is noteworthy that researchers conducted the first human trial of germline target control strategy by evaluating the safety and immune response of germline targeted priming vaccine candidate eOD-GT8 60mer (combined with adjuvant AS01B) in the IAVI G001 Phase 1 clinical trial.. The vaccine immunogen is a self-assembling nanoparticle containing 60 fragments of the engineered ectodomain of HIV gp120, germline targeting version 8 (eOD-GT8), genetically fused and arranged on the inner nanoparticle. eOD-GT8 was designed to have affinity for putative germline precursors of the VRC01 class of bnAbs, where distinct genetic and amino acid sequence signatures define a class of antibodies with distinct LC and HCDR3. In preclinical experiments, eOD-GT8 was shown to bind to a variety of VRC01-like human germline B cells with an average frequency of approximately 96% and considerable affinity [geometric dissociation constant (KD) of 4 μM]. The adjuvanted eOD-GT8 60mer was shown to be able to initiate VRC01 B-like cell responses in multiple different engineered mouse models, including rigorous models that mimic two key parameters of human vaccination: precursor frequency and affinity, and was also shown to elicit VRC01-like responses that promote the development of bnAbs in mouse models. In addition, in the IAVI G001 trial, researchers also determined the effectiveness of human immunization in inducing VRC01 class immunoglobulin G (IgG) B cell responses.
Figure 3 Hierarchical clustering and genetic diversity of VRC01 class BCRs.
[Vaccine Performance Evaluation]
In human clinical trials, all but one study participant received both vaccines. In all trial situations, no serious adverse events (AEs) occurred, and no participant became infected with HIV-1 or became HIV seropositive. However, 97.9% of the subjects experienced local or systemic adverse events, but they were generally mild or moderate. In most cases, they could be relieved within 1 to 2 days, which is consistent with other vaccines. These results show that the vaccine is safe and tolerable for human application.. After the first dose, all vaccinees developed serum IgG-binding antibodies against the eOD-GT860mer and monomer as well as the eOD-GD8 CD4 binding site (CD4bs) epitope, which binds eOD-GC8 more strongly than eOD-GP8-KO11, an epitope knockout mutant that blocks binding of VRC01 class precursor Abs and bnAbs. After the second vaccination, vaccine-induced eOD-GT860mer and monomer responses increased, while CD4bs-specific responses remained relatively constant. Combined with preclinical experiments, studies showed that the vaccine was highly immunogenic and induced class-switching, antigen-specific and CD4bs-specific serum IgG responses.
Figure 4 Amino acid mutation levels in the HC and LC V genes of VRC01 and non-VRC01 grade BCRs in vaccine recipients over time.
In addition, the researchers found that VRC01-like responses were highly polyclonal, with different HCDR3 and LC. Hierarchical clustering of BCR sequences showed that in 2865 vaccination trials, 1779 independent clusters derived from independent germline recombination events had VRC01-like BCRs, and 60% of VRC01-like responses originated from different precursors . There are practical limitations to the depth of sampling of the CD4bs-specific BCR gene repertoire, and deeper sampling may have identified additional clusters or members for each cluster. Nonetheless, the number of independent VRC01 class clusters per participant was quite high (median and were 32 and 65 in the low-dose and high-dose groups, respectively) (Figure 3E), thus suggesting a large number of distinct precursors in each individual. We detected a high degree of VRC01-like polyclonality in memory B cells and PBs at all stages after priming and enhancement, i.e., eOD-GT8 60mer initiated responses from different regions of VRC01-like precursors and maintained clonal diversity after enhancement .
[Summary and Outlook]
Vaccines inducing antibodies with predefined genetic characteristics and binding specificity are of great significance for the prevention of viruses with high antigenic diversity, such as HIV, influenza, hepatitis C virus, and betacoronavirus. The development of vaccines that can sustainably induce similar bnAbs, combined with broad T cell immunity, is expected to achieve prevention of these pathogens. Based on these concepts, this study establishes clinical proof-of-concept for a germline-targeted vaccine design launch strategy by integrating bioanalysis and human clinical trials, supports the development of enhanced vaccine regimens to generate VRC01-like bnAb responses against HIV, and confirms that the germline targeting strategy can be applied to other targets of HIV and more other pathogens. This study is an important advance in the development of preventive vaccines that can trigger VRC01 class CD4bs bnAbs. At the same time, researchers are continuing to work on triggering bnAbs to other HIV epitopes. The successful development of an effective HIV vaccine will require bringing all these research strands together into a multi-layered, multifunctional approach to immunization. Taken together, this study provides a groundbreaking proof-of-concept for a targeted preventive strategy for HIV vaccines in human clinical trials.
Article source:
https://www.science.org/doi/10.1126/science.add6502
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