A team of researchers shared in November 2023 that their study, published in Nature Medicine, has provided insight into the longevity of neutralising antibodies (nAbs) in HIV-1 infected people. Despite the assumption that an HIV-1 vaccine “can only be effective” if it produces these antibodies in vaccinated people, no neutralising antibody-eliciting vaccines are yet available. Therefore, only data from “HIV-1 neutralisers – persons with HIV-1 who naturally develop broad and potent nAbs – can inform” research.
The team therefore assessed HIV-1-neutralising immunoglobulin G (IgG) from 2,354 persons with HIV-1, either on or off antiretroviral therapy. The results indicate that these responses can persist for “several years”, even at low antigen levels, from which the researchers infer that an HIV-1 vaccine “may elicit a durable nAb response”.
Getting to know nAbs
The authors state that neutralising antibodies (nAbs) block viral infection by “directly binding circulating viruses, thus preventing these viruses from infecting their intended target cells”. Furthermore, they can “eliminate infected cells” through “antibody-mediated effector functions”. Therefore, they are “crucial” to “preventing and overcoming viral infections” and are considered “one of the most important correlates of vaccine-mediated protection”.
In HIV-1 infection, elicited circulating antibodies are reportedly “mostly strain-specific” and unable to prevent replication of the “broad diversity of viral strains” that evolves in a person who is infected with HIV-1. However, broadly neutralising antibodies (bNAbs) targeting “up to 99% of tested HIV-1 variants” have been isolated from persons with an “extraordinary HIV-1 neutralising serum response. The authors refer to “elite neutralisers”, with “elite activity” previously defined as the “ability to neutralise, on average, more than one pseudovirus at an IC50 titer of 300 within a clade group and across at least four clade groups”.
These bNAbs have shown an ability to prevent infection in mice and nonhuman primate models. Additionally, research into two multicentre trials revealed that intravenous infusions of the bNAb VRC01 were “associated with reduced incidence of infection by VRC01-sensitive HIV-1 strains”. Despite this, there was no greater protection from HIV-1 acquisition overall in comparison with placebo. It is understood that “serum titers and the potency against infecting strains of passively infused bNAbs correlate with protection from HIV-1 infection”.
What does this mean for vaccines?
Considering available research, the authors suggest that a vaccine that can elicit “potent and borad nAbs in humans at high titers could effectively protect from HIV-1 infection”. Thus, the induction of nAbs is a “main goal” for vaccine development. The paper recognises the development of “several” vaccine candidates and strategies. However, there are challenges to overcome, and information on the “durability and dynamics” of nAb responses in humans will be “highly relevant” for these strategies.
What does the study do?
The paper explores the results of the “largest international study” of HIV-1 neutralisation dynamics, sampling over 2,300 individuals. Through IgG isolation, the team “determined the neutralising activity” in participants on and off ART, assessing the “association between different levels of viral replication” and nAb responses.
- Determine factors driving IgG-neutralising activity
- Describe the neutralisation activity of highly potent elite neutralisers
- Longitudinally decipher the nAb activity in response to different viral load dynamics
Study findings and implications
The authors suggest that for “many” infections and vaccines the dynamics of nAb responses are “well-studied” and knowledge about nAb durability can inform vaccination regimens. However, in the absence of an effective HIV-1 vaccine and considering that “only a few people develop a potent neutralising response” during natural infection, knowledge about the “durability of naturally developing anti-HIV-1 nAb responses” is “missing”. While there are “promising” candidates in development, it is “unclear” how long vaccine-induced nAb responses would last and offer protection.
In the cohort, involving HIV-1-infected persons from “various countries” (Cameroon, Germany, Nepal, and Tanzania), the researchers identified “several factors” as “independent predictors for better IgG neutralisation”. To understand the changes in nAb response over time in response to different levels of viral replication, they conducted a longitudinal study of individuals with potent HIV-1-neutralising IgG activity.
The nAb half-lives in individuals with no- and low-level viraemia were 9.3 years and 16.9 years. At 4.0 years, half-life was “considerably shorter” in individuals who initiated ART and therefore experienced a suppression of their viraemia during the follow-up period. Thus, neutralising serum responses are “relatively stable” over time, even without “large amounts of stimulating antigen”.
“If effective nAb-inducing vaccines are available in the future, our data indicate that nAbs can be rather long-lived even if the vast majority of the stimulating antigen vanishes over time.”
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