In January 2024 Uvax announced that the first participant in a Phase I clinical trial to evaluate the company’s HIV-1 vaccine candidates has been dosed. The first-in-human clinical trial will evaluate two different regimens of UVAX-1107 and UVAX-1197 in 34 healthy volunteers in Australia. UVAX reports that the primary endpoints will measure safety and immunogenicity after the primary and boosting dose series being evaluated in parallel arms. It will also assess whether either vaccine, or a combination of both, produces the “optimal immunological response”.
UVAX vaccines in trial
UVAX-1107 and UVAX-1197 are based on the company’s proprietary 1c-SApNP® technology, displaying 20 uncleaved, prefusion-optimised (UFO) HIV envelop (Env) trimers in glycan-trimmed and wild-type forms, respectively. UVAX-1107 has a portion of the glycan shield through glycan trimming, an enzymatic removal of glycans to allow better access to the conserved neutralising epitopes. By comparison, UVAX-1197 retains the wild-type glycan shield.
In a preclinical toxicology study, both vaccines were shown to be safe with no serious adverse events and consistent with previously approved protein-based vaccines. A second preclinical study demonstrated that they “elicited robust neutralising antibody responses against the vaccine-matched virus in 99% of the animals”. Preliminary screening assays also demonstrated “appreciable neutralisation” in serum when tested against a panel of primary HIV-1 isolates.
Meeting an unmet need
Dr Ji Li, CEO of Uvax, commented on the “tremendous unmet need” for a vaccine to protect against HIV-1 infection.
“UVAX-1107 and UVAX-1197 represent an advancement in HIV vaccine technology with industry-recognised innovations in our design and delivery and delivery.”
Dr Li is “proud” of the team for bringing these “promising” vaccine candidates into human testing, which is a “significant milestone”.
In January 2024 IAVI announced a collaboration with ReiThera Srl and the Ragon Institute to develop a novel HIV vaccine candidate. This work will be funded by the Bill & Melinda Gates Foundation, with each partner bringing expertise and experience; the vaccine will comprise ReiThera’s GRAd vector and T-cell epitopes identified by the Ragon Institute. The collaboration has entered the “manufacturing phase” to produce the clinical trial material.
The partners will cover different aspect of the programme:
ReiThera will perform vector engineering and generation, process development, and good manufacturing practice manufacture and release for the clinical use of the vaccine.
The Ragon Insititute will lead preclinical development.
IAVI will sponsor and execute a Phase I clinical trial to evaluate the safety and immunogenicity of the candidate.
“The research is aimed to primarily benefit those in lower- and middle-income countries, particularly in Africa, who are disproportionately impacted by HIV and lack access to suitable prevention options.”
Key partners include teams from the Africa Health Research Institute (AHRI) and the National Institute for Communicable Diseases (NICD) in South Africa and the Mutala Trust and Charles River Medical Group (CRMG) in Zimbabwe.
Ragon’s research meets ReiThera’s platform
IAVI states that “prior findings” by the Ragon Institute have shown that “mutation of residues at important network positions disproportionately impaired viral replication and occurred with high frequency in epitopes presented by protective human leukocyte antigen (HLA) class I alleles”. Furthermore, CD8+ T-cell targeting of “highly networked epitopes” distinguished people who “naturally control” HIV, even in the absence of protective HLA alleles.
The target, therefore, is the development of a vaccine component that generates a “broadly protective potent CD8 T-cell response” for “mutationally constrained” epitopes. This will be applied with ReiThera’s novel platform, which uses a proprietary replication-defective Gorilla adenoviral (GRAd) vector. This belongs to species C adenoviruses, considered “among the most potent vaccine carriers” for the purpose of inducing CD8 T-cell responses to encoded antigens, with a low seroprevalence in humans.
The platform was chosen based on evidence from preclinical and clinical studies, in which it demonstrated a “strong” induction of T-cell responses to the encoded antigens and a “very low” frequency of anti-GRAd pre-existing immunity in humans.
Dr Stefano Colloca is ReiThera’s Chief Technology Officer and co-Founder and looks forward to “collaborating with IAVI and the Ragon Institute” to continue to “advance our shared vaccine commitment to address the global challenges posed by HIV”.
“The funding validates the potential of our novel GRAd vector technology to develop vaccine candidates stimulating a strong T-cell response.”
Dr Gaurav Gaiha from the Ragon Institute is “thrilled to have the opportunity to collaborate with ReiThera and IAVI” to take the GRAd-HIV highly networked T-cell vaccine candidate “towards clinical evaluation”.
“We are particularly pleased that this takes place with partners in sub-Saharan Africa, given the immense need for new solutions to curtail the ongoing HIV epidemic.”
Dr Sangeetha Sagar, IAVI’s Vice President of Product Development, said that IAVI’s Product Development Centre (PDC) is “so pleased to be able to partner with ReiThera and the Ragon Institute”.
“The PDC’s purpose is to advance promising biomedical innovations across the global health field by supporting clinical testing and product development, and we are excited to have the opportunity to support this new approach to HIV vaccine development.”
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.
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.”
In September 2023 Vir Biotechnology announced that the first participant in a Phase I trial has been dosed. The trial of VIR-1388 will evaluate the safety, reactogenicity, and immunogenicity of the investigational novel T cell vaccine for the prevention of human immunodeficiency virus (HIV). Initial data from the trial are expected in the latter half of 2024.
VIR-1388
VIR-1388 is an investigational subcutaneously administered HIV T cell vaccine based on the human cytomegalovirus (HCMV) vector platform. It is designed to elicit “abundant” T cells that recognise several HIV proteins in a different way to that of previous vaccine efforts. VIR-1388 applies lessons from VIR-1111, an investigational proof-of-concept vaccine, with the goal of creating a safe and effective HIV vaccine.
The vector is a weakened version of the virus, designed to deliver the vaccine material to the immune system “without causing disease” in participants. HCMV has been present in “much of the global population for centuries”, with most people experiencing no symptoms and being unaware of infection. It remains detectable in the body for life. Thus, the team at Vir believe it could deliver and help the body retain vaccine material for a long period.
The trial
The Phase I trial is randomised, double-blind, and placebo-controlled evaluation of the safety, reactogenicity, and immunogenicity of three different doses of VIR-1388 compared with placebo. It is expected to enrol around 95 participants between the ages of 18 and 55 who are not living with HIV, with existing antibodies specific to HCMV, and in overall good health.
The study comprises two parts; Part A is a lead-in phase enrolling a limited number of HCMV-positive patients of non-childbearing potential with a frequent safety monitoring schedule. The second part, Part B, expands enrolment to a broader population of HCMV-positive patients, including persons of childbearing potential. An optional long-term follow-up study will increase participation for up to three years after the first dose.
The trial is supported by NIAID and the Bill & Melinda Gates Foundation. It takes place across international sites within the federally funded HIV Vaccine Trials Network (HVTN).
A major challenge and a clinical milestone
UNAIDS estimates that in 2021 around 1.5 million people were newly infected with HIV, with around 650,000 dying from AIDS-related deaths. Dr Carey Hwang, Vir’s Senior Vice President, Clinical Research, Head of Chronic Infection, describes HIV as a continued “major global public health challenge” that persists despite “decades of research efforts”.
“The initiation of our first clinical trial evaluating VIR-1388 is an important clinical milestone in our pursuit of developing an HIV vaccine.”
Dr Hwang hopes that the “unique approach” will “help close the longstanding public health gap in HIV prevention”.
In a statement from the University of Oxford in July 2023 it was announced that preliminary analysis of vaccine trial results demonstrates the induction of “high frequencies” of broadly specific T cells. These cells recognise “functionally conserved regions on HIV-1 and are consequently “more protective”. The statement indicates that “not all T cells are equally protective”, with the T cells induced by the vaccine candidate, often “underutilised in natural HIV-1 infection. These T cells, known as killer T cells, could inhibit four major global HIV clades: A, B, C, and D. Further analyses continue, with first results expected in a publication later in the year.
HIV-CORE 006
The goal of the trial is to evaluate the safety, tolerability, and immunogenicity of the novel mosaic HIV vaccine candidate, HIVconsvX. It has been designed to target a broad range of variants, which could allow application for strains in any geographical region. Unlike many other candidates, which aim to generate antibody or T cell responses against more variable HIV epitopes, HIVconsvX aims to “induce the immune system’s killer T cells against a group of highly conserved regions”. These “obliterate the virus factories in the body”.
HIV-CORE 006 is a Phase I double-blind, placebo-controlled trial. Mosaic immunogens are delivered by a prime-boost regimen of non-replicating simian adenovirus, followed by non-replicating poxvirus MVA. Volunteers, comprising up to 88 healthy African adults between the ages of 18 and 50, who are HIV-uninfected and deemed at low risk of infection, were either given the vaccine regimen or placebo at 2 visits 4 weeks apart. The trial took place across four vaccine trial sites in Kenya, Uganda, and Zambia.
GREAT work
The trial is the work of the GREAT team from 8 organisations in Europe and Africa, led by Professor Tomáš Hanke of the Jenner Institute. The team comes from Imperial College London, IAVI, KAVI-Institute for Clinical Research, KEMRI-Wellcome Trust Research Programme, the Medical Research Council at the Uganda Virus Research Institute on AIDS, the UVRI-IAVI HIV Vaccine Programme in Uganda, and the Centre for Family Health Research in Zambia. The programme is supported by the European & Developing Countries Clinical Trials Partnership.
Professor Hanke commented that the study team has evaluated a “highly rational, bioinformatics-assisted vaccine design to address the enormous variability of HIV-1″. This is one of the “greatest challenges to the development of an effective vaccine against HIV/AIDS”, he says.
“The analysis so far indicates the induction of strong and multi-specific T cell responses that recognise several vulnerable parts of proteins common to most HIV variants in each individual at the same time – targeting HIV where it hurts.”
Dr William Kilembe, Project Director at the Centre for Family Health Research in Zambia, recognised that the GREAT consortium “leveraged international partnerships” in Africa and Europe to test the vaccine in the communities where it would “ultimately have the greatest public health impact”.
“Through this trial, the consortium members have contributed to strengthening the capacity of the partnering clinical research centres to conduct robust HIV vaccine research and clinical trials.”
“Community engagement is key to this approach, and we look forward to continuing to work with community stakeholders as the final results become available.”
An important step
Dr Vincent Muturi-Kioi, Senior Medical Director at IAVI, said that the study represents an “innovative hypothesis” to “harness the killer T cell arm of the immune system”.
“It’s important that we have a diversity of vaccine candidates in the pipeline to make sure we have the greatest chance of success in developing an effective HIV vaccine.”
Dr Paola Cicconi, Senior Clinical Researcher at the Jenner Institute, was pleased that the vaccines used in trial “demonstrated a favourable safety profile” as well as the induction of an immune response in “most of the participants”.
“These are promising results, and an important step in developing an HIV vaccine that can protect people against HIV infection in all parts of the world.”
The next stage will be the release of primary findings later in the year and additional analyses.
Do you think the approach could lead to a greater step forward than previous vaccine candidates? To hear a little more about the challenges associated with HIV vaccine development, check out our interview with Dr Gaurav Gaiha from the Congress in Washington earlier this year.
Continuing our series of exclusive Congress interviews we are delighted to share a conversation with Dr Gaurav Gaiha at the Congress this month. Dr Gaiha participated in the HIV workshop on the pre-Congress day, presenting “highly networked” CD8+ T cell vaccines for HIV. In our chat we found out more about the challenges associated with developing vaccines for HIV, and how Dr Gaiha and his team are tackling them. We are grateful for his time, and hope that you enjoy the interview!
Introducing Dr Gaiha
As Dr Gaiha tells us, he runs a research laboratory that is focused on infectious diseases and translating protective T cell response findings into vaccines. Additionally, he sees patients at the general hospital.
“So really trying to both work on research advancements but also kind of serve people in a very direct patient-doctor relationship.”
More on “highly networked” approaches
As we know, Dr Gaiha was at the Congress to present on “highly networked” CD8+ T cell vaccines. We therefore asked him to give us a little insight into this approach. He explains that this is an approach that acknowledges the “immense diversity” of HIV and its “incredible” capacity to mutate in response to immune pressure. It uses insights from computational biology and network theory to identify the “critical parts” of the HIV cells that can’t mutate: vulnerable regions.
“If you imagine a network, like a social network, there’s going to be certain ‘key players’ in that social network, where if you were to remove them it would really be damaging to how that social network stays connected.”
This social network analogy is really helpful in the digital age! So, at the level of the HIV proteins, Dr Gaiha and his team are trying to direct T cells towards those “key players”. If the virus tries to mutate it will have a “consequential effect” on the virus’ capacity to replicate.
“Hit the virus where it hurts.”
Challenges for HIV vaccines
When we spoke to Dr Feinberg a few months ago, he described HIV as one of the most “vexing” challenges that vaccine developers are tackling. We asked Dr Gaiha what challenges he identifies, and how he and his team are approaching them. He identifies “several” challenges, two of which he has already mentioned: diversity and adaptability.
From a T cell perspective, there’s a human challenge – “we as humans are diverse”. Therefore, trying to get a “one size fits all” vaccine is a difficult pursuit. Furthermore, there’s the issue of durability. If the immune response dips, the virus can sometimes “break through”.
What Dr Gaiha’s team is trying to do is “hit at the diversity” and “hit at that ability for the virus to mutate”.
“We’ve made strides.”
Now, they are looking to make the immune responses durable and ensure that they “get to the right sites of the body”.
What about access?
As we know, current HIV therapeutics are a lifelong and often burdensome addition to patients’ lives. Could a vaccine overcome some of these issues? Dr Gaiha recognises that enabling access and subsequently encouraging continued uptake of drugs is a challenge. A preventative vaccine would be “fantastic”, obviously, but in the meantime, a therapeutic vaccine that could “suppress the virus” would be a “huge development”.
“HIV is one of those viruses where vaccine development is very much in line with addressing this issue of access.”
What did we take from COVID-19?
Many of our speakers have been working in their fields since before COVID-19, including Dr Gaiha. We asked him if, in his opinion, there are any lessons that we can transfer from our experience of dealing with the pandemic.
“The biggest has been our experience with the RNA vaccines.”
Dr Gaiha believes that we can translate some of our RNA vaccine lessons from COVID-19 into effective and immunogenic HIV vaccines. Furthermore, “because they can be generated so rapidly”, more “iterative developments” can be facilitated in HIV.
“It’s been such a struggle to find the right pieces.”
Another lesson Dr Gaiha hopes to take forward is the “urgency that made it happen”.
“I think we really should be trying to apply that same urgency to the HIV problem.”
Although every “small, incremental” step forward is a worthy achievement, Dr Gaiha is hoping to take the “same mindset and approach” that will spur vaccine development to the “next level”.
Why WVC?
We asked Dr Gaiha what brings him to the Congress, and he kindly gave us an insight into what he was looking forward to over the few days he was with us. He was enthusiastic about the opportunity to be in-person once again, despite the obvious comfort of remote connections!
“The informal exchange is just such a wonderful thing.”
Another benefit is the range of “different perspectives” and Dr Gaiha was looking forward to engaging with these different perspectives and possibly forging some new collaborations.
We are so grateful to Dr Gaiha for his work and hope that you enjoyed his insights as much as we did! For more information on what went on at the Congress, click here to download the post-Congress report. Finally, make sure you subscribe to stay in the loop for future interviews!
In February 2023 LinKinVax announced positive interim results from the ANRS VRI06 Phase I trial, evaluating a preventative HIV vaccine. This was conducted by sponsor INSERM-ANRS and the Vaccine Research Insititute. LinKinVax reports that the candidate is “safe” and “induces an early, significant, and sustained immune response”.
CD40.HIVRI.Env
The vaccine candidate is developed by the Vaccine Research Institute (VRI) with LinKinVax technology, the first vaccine based on this technology, targeting an immune response binding HIV envelope protein to monoclonal antibodies specifically targeting CD40 receptors on dendritic cells. The Env protein is injected and “delivered directly” to the dendritic cells. The vaccine is combined with the Hiltonol adjuvant, “designed to enhance its potential action”.
Professor Yves Lévy, Executive Director of the VRI and CMSO of LinKinVax, explained that the candidate has done well so far, with the “immune response profile” it generated being “associated with a reduced risk of HIV infection in the RV144 trial”.
“However, at this early stage of vaccine development, it is important to remember that volunteers should continue to protect themselves from any risk of HIV infection, as the efficacy of the vaccine will only be evaluated in the Phase II/III studies.”
The study
The ANRS VRI06 clinical study was conducted in France and Switzerland and included 72 healthy volunteers. Safety and immunogenicity were assessed at Weeks 6, 26, and 48, with results suggesting that it is “safe and well tolerated”.
Dr André-Jacques Auberton-Hervé, Co-founder and CEO of LinKinVax is “pleased” with the “promising immunogenicity results, which demonstrate the robustness of our DC Targeting vaccine platform and confirm its safety”.
“This important milestone paves the way for the upcoming Phase II/III clinical studies that we will conduct once the final Phase I results have been obtained. These studies will aim to demonstrate the efficacy of the vaccine, the ‘Everest of vaccine strategies’, which has been the elusive goal of HIV research for the past 40 years.”
For more on HIV vaccine updates, join us at the World Vaccine Congress in Washington this April.
In January 2023 Janssen and global partners announced the results of an “independent, scheduled data review” of a Phase III Mosaico study of Janssen’s investigational HIV vaccine regimen. The Data and Safety Monitoring Board (DSMB) established that although there were no safety issues with the vaccine regimen, it was ineffective in preventing HIV infection compared to placebo. Consequently, the Mosaico clinical trial will be discontinued.
Mosaico
The study began in 2019 and completed vaccinations in October 2022. It enrolled “approximately 3,900 cisgender and transgender people who have sex with cisgender men and/or transgender people”. This group represented populations “vulnerable to HIV”. The trial took place across 50 sites.
The study evaluated an investigational vaccine regimen of a mosaic-based adenovirus serotype 26 vector (Ad26.Mos4.HIV). This was administered during 4 vaccination visits throughout one year. A mix of soluble proteins, adjuvanted with aluminium phosphate, was also administered during visits 3 and 4.
A statement from the US NIH identified “funding support” from NIAID and “additional study support” from the US Army Medical Research and Development Command.
DSMB analysis
Using currently available data the analysis revealed that the regimen “does not protect against HIV and the study is not expected to meet its primary endpoint”. This comes after the primary analysis of the Phase IIb Imbokodo study, in which a similar investigational regimen did not provide adequate protection against HIV in young women.
As a result of this determination, the trial is to be discontinued and participant notifications are underway.
A disappointing outcome
Dr Penny Heaton of Janssen is “disappointed with this outcome” but emphasised that the organisation stands “in solidarity” with those “vulnerable to and affected by HIV”. She acknowledged “significant advances in prevention” but referred to the 1.5 million people who acquired HIV in 2021 as evidence of the “unmet need for new options”.
“We remain steadfast in our commitment to advancing innovation in HIV, and we hope the data from Mosaico will provide insights for future efforts to develop a safe and effective vaccine.”
For discussion on the future of HIV vaccines at the World Vaccine Congress in April, get your tickets today.
HIV is widely considered to present the scientific community with a “daunting scientific challenge”, as stated by Dr Anthony Fauci in 2022. However, a recent publication in Science Translational Medicine reveals positive results from a primate study.
The publication states that a “challenge” to the development of an HIV vaccine is the “need to induce a polyclonal neutralising antibody (nAb) response in vaccine recipients”. Dr Barton Haynes of Duke School of Medicine, speaking to Technology Networks, suggests that this is because of the “similarity of the Env regions of HIV” as well as the “complexity of the antibodies that are required to interact with Env-neutralising sites”. For him, this is the “most difficult vaccine problem of all tried to date”.
The recent primate study by researchers at Duke investigated the potential offered by a “stabilised HIV-1 envelope trimer mixed with a Toll-like receptor 7/8 agonist”. This is an adjuvant used in vaccines against hepatitis B, EBV, and varicella zoster. The results demonstrated that macaques that had been vaccinated with this candidate “developed potent nAbs that targeted multiple sites on the envelope, including the CD4 site”. Thus, protection against “mucosal simian-human immunodeficiency virus” was afforded. Dr Haynes states that “HIV does not grow well in monkeys”, so “SHIV” can be used to “test an HIV envelop vaccine”.
This might be the “first step” in the production of a successful candidate, according to Haynes. Clinical trials are set to begin shortly to see if this vaccine can boost a similar candidate.
“My hope is that current studies identifying the specific steps needed for broadly neutralising and protective antibodies will teach us not only to make a successful HIV vaccine, but also teach us how to engineer the immune system for making many difficult-to-make vaccines”.
To learn more about HIV vaccine candidates get your tickets to the World Vaccine Congress in Europe, 2022.
In August 2022 an article for NAM’s Aidsmap detailed the approval of Gilead Sciences’ long-acting HIV capsid inhibitor lenacapavir. Marketed as Sunlenca, it’s a twice-yearly antiretroviral indicated for “treatment-experienced people with multi-drug resistant HIV who cannot otherwise construct a fully suppressive regiment”.
Gilead Sciences stated that lenacapavir is a “first-in-class capsid inhibitor with a multi-stage mechanism of action”. With no known cross resistance, it offers a six-monthly treatment option for “people with HIV whose virus no longer effectively responds to their current therapy”. Dr Jean-Michel Molina, Professor of Infectious Diseases, described the “critical unmet need” that lenacapavir would be able to fill.
“Lenacapavir provides an innovative long-acting HIV therapy option with potential to transform the clinical landscape”.
Lenacapavir
Previously known as GS-6207, lenacapavir disrupts the HIV capsid. It has a long half-life in the body, which enables subcutaneous injection once every six months. However, it must be taken in combination with other antiretrovirals, as oral medications. Before lenacapavir programmes begin, a tablet formulation is used for a fortnight’s “loading period” to create a foundation before the long-acting injections.
Sunlenca
Sunlenca uses a “multi-stage mechanism of action”, which distinguishes it from other antiviral agents. In addition, it provides a “new avenue” for treatment of individuals with multi-drug resistant HIV. Sunlenca is designed to inhibit HIV at “multiple stages of its lifecycle” rather than just one stage of viral replication. It is indicated in the EU for the treatment of adults in combination with other therapies.
CAPELLA
The CAPELLA study evaluated lenacapavir in combination with an “optimised background regimen in people with multi-drug resistant HIV who are heavily treatment-experienced”. Gilead described the study as a “double-blinded, placebo-controlled global multi-centre study”. It was designed to “evaluate the antiviral activity of lenacapavir”. When administered every six months as subcutaneous injection lenacapavir “achieved an undetectable viral load” at week 52 for 83% of participants. The study took place across North America, Europe, and Asia.
Daniel O’Day, Chairman and CEO of Gilead Sciences, described this as an “innovative new option for long-acting care”.
“Lenacapavir is a unique and potent medicine with the potential for flexible dosing options”.
He suggested that a long-term goal is to “deliver multiple long-acting options in the future” in the quest to make a “fundamental difference” to “end the HIV epidemic”.
Although this recent authorisation applies to the 27 member states of the EU, Norway, Iceland, and Lichtenstein, the FDA put a clinical hold on lenacapavir. Due to concerns about the glass vial used for injectable formulation, it was not approved. However, this hold was lifted in May 2022. Gilead submitted a new drug application after changing the glass. A decision from the FDA is expected within a year.
A study published in Nature in August 2022 stated that research into curing HIV focuses on “reactivating latent proviruses to enable elimination by CD8+ cytotoxic T-cells.” In recent research by scientists from the USA and Canada, they found that the mRNA vaccine BNT162b2 “activates the RIG-=I/TLR – TNF – NFκb axis”. This resulted in “transcription of HIV proviruses with minimal perturbations of T-cell activation and host transcription”.
They observed that T-cells specific to “early gene-product HIV-Nef” demonstrated increased frequency and effector function in lifelong antiretroviral therapy (ART) treated patients following the vaccination. Furthermore, they noted “significant decreases in cell-associated HIV mRNA”, which they concluded suggested “killing or suppression of cells transcribing HIV”.
The study states that although ART has “transformed” HIV into a “manageable chronic condition” there is still no safe cure with demonstrable success. The authors note that identifying “meaningful latency reversal” is “confounded” by the fact that HIV RNA “does not necessarily equate to antigen expression”. Thus, investigating CD8+ T-cells might be the key to “assessing whether these cells have been engaged”.
Previous studies indicated that vaccination influences HIV latency, but mRNA vaccines had not been explored in such detail. In this most recent study, the Pfizer/BioNTech mRNA Covid-19 vaccine (BNT162b2) was linked to “innate immune sensing of mRNA and downstream activation of NFκb”. This took place without recorded T-cell activation and with limited perturbation of the host transcription. By contrast, the influenza vaccine that they compared it to “induced robust T-cell activation and host transcriptional changes, without detectable HIV reactivation” in assay.
“The observations presented here advance the shock and kill concept, by providing evidence for the productive engagement of HIV-specific T-cells with their antigens in ART-suppressed donors following receipt of an mRNA vaccine”.
The authors acknowledge that mRNA vaccines that target HIV antigens are under development for prophylactic and therapeutic capacities. Their results indicate that “innate immune sensing of the mRNA vaccine platform” may contribute to therapeutic outcomes by “acting as a built-in LRA” (latency reversal agent).
The results indicate the importance of measuring “granzyme-B-producing Nef-specific responses in latency reversal studies”. They also “add impetus to developing HIV-targeted mRNA therapeutic vaccines that leverage built-in LRA activity”. The study suggests that HIV cure research can advance using the results of the paper. The authors hope that this will enable the field to continue working towards “reductions in HIV reservoirs”. This is an important development for the industry, but more importantly, for the 37.7 million people living with HIV.
To learn about innovations in HIV vaccine technology from Dr Brander of AELIX Therapeutics at the World Vaccine Congress in Europe 2022 follow this link.
In July 2022 China’s drug regulator gave conditional approval for Azvduine, an HIV drug developed by Genuine Biotech, to be used in the treatment of Covid-19. Specific data from clinical trials were not released but the company announced that in a Phase III clinical trial around 40% of participants showed “improved clinical symptoms”. Safety and further efficacy information remain unpublished.
Despite this absence, experts are confident that Azvudine’s status as an approved HIV treatment enabled a fast-tracked application. They say that Azvudine will “trick the virus’ polymerase into incorporating the drug into its RNA”. This prevents viral replication.
The need for Covid-19 therapies is growing, and until the approval of Azvudine China had only authorised one other oral antiviral: Paxlovid. This was developed by Pfizer and is highly effective. However, it is accompanied by suggestions of a “rebound” in symptoms following course completion. Despite this, it reduces the risk of hospitalisation and death by almost 89%, and was the treatment recommended by White House doctors for President Joe Biden in his recent recovery from the virus.
Another Chinese oral antiviral (VV116) is currently in final development stages. It is “a pill version of the intravenous drug remdesivir”, which is produced by Gilead Sciences. The developers, Shanghai Junshi Biosciences, intend to apply for regulatory approval shortly. They suggest that Phase III trials demonstrated faster and more effective results when compared with Paxlovid. Again, detailed data is yet to be released and it is “unclear whether it will outperform Paxlovid”. All of these antivirals work best when administered as close to infection as possible.
With these antiviral developments we might expect to see an alleviation of China’s meticulous “zero-Covid” policy. This policy involves rigorous testing and quarantine regulations. However, Dr Jun Wang of Rutgers University suggests that the lifting of regulations is unlikely, certainly while access to these treatments is limited. With more treatments moving along the pipeline towards approval, will we see increased availability to the Chinese public?
To participate in a discussion of Antivirals and Vaccines at the World Vaccine Congress in Europe 2022, click here.
In March 2022 Dr Anthony Fauci, director of NIAID, reflected that developing an effective HIV vaccine is a “daunting scientific challenge”. He identifies the obstacles: genetic variability, ability to establish lifelong infection, and human inability to clear HIV independently. However, he was optimistic that the success of the Covid-19 vaccines offers “an exciting opportunity to learn whether mRNA technology can achieve similar results against HIV infection”.
Dr Mark Feinberg, president and CEO of IAVI, believes it will. He looks forward to the “safe, effective, affordable, and durable” vaccine potential of mRNA. IAVI and Moderna partnered with each other to use this technology. Stephane Bancel, CEO of Moderna, hopes that a “novel approach” might encourage progress. In January 2022 Phase I trials began in Washington DC.
Another development is HTI, which Dr Christian Brander of AELIX Therapeutics discovered with his team.* They based this on the observation that T-cell responses to some HIV regions are enriched in the cases of individuals with enhanced control of their infection. The immunogen brings these regions together. The sequence design uses data from around 1,000 patients with HIV infection. The predictive power of HTI directed T-cell responses has been validated through sub-studies in earlier vaccine trials. Preclinical data demonstrated that immunisation with HTI in mice and macaques provoked a strong and broad T-cell response. As of July 2022, HTI is still in Phase II trials in Spain.
As we explore these options, hope continues to grow for the estimated 37.7 million living with HIV. The WHO global health sector strategy intends to reduce HIV infections from 1.5 million in 2020 to 335,000 by 2030. Likewise, they predict that deaths will decrease from 680,000 in 2020 to under 240,000 in 2030. With concerted vaccine efforts, this strategy might become a reality across the globe.
To read more about the necessity of HIV vaccine development click here.
*To hear from Dr Brander at the World Vaccine Congress in Europe 2022 follow this link.
In an article for npj vaccines, a group of experts present an approach to effectively and efficiently evaluate vaccines against antimicrobial-resistant (AMR) pathogens. The approach, which they call Reverse Vaccine Development, evaluates proof-of-principle efficacy “as early as possible” in a population with a high incidence of disease. The authors suggest that their method “may be the only way” to deliver life-saving vaccines to populations affected by AMR-pathogen diseases at incidences that are “typically low and unsuited” to Phase III efficacy trials. Here, we examine the proposal and invite you to share your reactions to it.
The burden of AMR and the need for vaccines
The paper states that a “recent estimation” of the burden of AMR on global human health indicates a “medical need comparable and likely larger than HIV and malaria”. In response, the vaccine community is targeting AMR pathogens. However, the development of these vaccines is “being hindered” by a “lack of understanding of their correlates of protection”.
“Vaccine development can be long, difficult, and costly. However, it becomes easier when a correlate of protection is known.”
The recent example of SARS-CoV-2 vaccine development speed is attributed by the authors not only to the “extraordinary” efforts of companies and authorities, but also to the knowledge of the “likely mechanism of protection”: “antibody to the spike protein preventing interaction with the host cell”. In contrast, for many of the human pathogens, including WHO’s list of global priority pathogens of antibiotic-resistant bacteria, the mechanism of protection “remains unknown”.
“Without a correlate of protection, late-stage clinical development is risky: many thousands of research participants may be needed for efficacy evaluations, and after many years of R&D and large expense, the trials may fail.”
Reverse Vaccine Development
The paper claims that, whilst developing a vaccine candidate against S. aureus, they identified a need for a “new vaccine development paradigm”, wherein data generation on efficacy and immune responses “should occur early”, instead of in Phase III. This starts with a Phase I/II study to assess safety, immunogenicity, and efficacy. If the vaccine is First-Time-in-Human (FTiH), a Phase I safety lead-in study could be needed to escalate dose. If there are no safety issues, the Phase II can “proceed to evaluate immunogenicity and efficacy”.
An important note is raised: the population used for the efficacy assessment must have a “high attack rate”. However, the attack rate may not be high in the population intended for registration. Thus, Reverse Vaccine Development “requires a population with a high attack rate” that is “available for study”. For example, the authors’ S. aureus vaccine candidate has such an available population: patients with a community acquired skin and soft tissue infection, for whom risk of recurrence is high.
“An efficacy evaluation of a candidate vaccine early in clinical development is of key importance. If the vaccine is found not efficacious, unnecessary exposure of subjects to the vaccine is avoided. If the vaccine is efficacious, correlates of protection can be explored.”
The success of Reverse Vaccine Development “depends on the number and validity” of the immunological readouts, and antibody titers in isolation are “likely insufficient”. The following “immunological parameters” are suggested:
Systems serology – offers unbiased and comprehensive data for identifying previously unappreciated processes and mechanisms.
Cellular responses – should be evaluated to understand the flavour of the induced T-cell response or if the vaccine increases the frequency of T cells specific for the vaccine antigens.
Transcriptional profiling – provides a complementary and broad view of the immune response to a vaccine.
Assessment of multiple immunological signals that correlate with each other – can increase the chance of identifying a signature of protection.
Assessment of memory responses.
Assessment of background immunity.
The authors suggest that Reverse Vaccine Development is “most suited” to the development of vaccines against pathogens for which a correlate of protection is not known, which hinders preclinical and/or clinical development.
What does this mean for the community?
The perspective concludes that the authors’ approach “assesses vaccine efficacy in the early phases” of development with the potential to identify a correlate of protection.
“Reverse Vaccine Development has the potential to facilitate the development of vaccines against AMR pathogens.”
How might this approach support your work or facilitate faster or more effective vaccine development? Vaccines for AMR pathogens were a key concern that arose at the Congress in Washington this April, so we expect to continue exploring this subject throughout the year with expert insights from our community. Don’t forget to subscribe to get these delivered to your inbox weekly.
In March 2024 The Bill & Melinda Gates Medical Research Institute (Gates MRI) announced the commencement of a Phase III clinical trial to assess the efficacy of the M72/AS01E tuberculosis (TB) vaccine candidate. The first doses will be administered in South Africa, where the disease “takes a heavy toll”. Gates MRI states that, if the vaccine is well-tolerated and effective it could potentially become the first vaccine to help prevent pulmonary TB in adolescents and adults and the first new TB vaccine in over a century.
The burden of TB
WHO estimates that 10.6 million people became ill with TB in 2022, with 1.3 million deaths: over 3,500 people died each day. The disease “primarily affects people in low- and middle-income countries”, with the people at highest risk “often living in poverty”. Gates MRI states that, in South Africa alone, around 280,000 people are diagnosed with TB each year. TB is “one of the world’s deadliest infectious diseases” and the “leading cause of death amongst people living with HIV”. However, the only available vaccine, BCG, was developed in 1921 and offers “inadequate protection” to adolescents and adults against the pulmonary form of the disease.
Dr Emilio A. Emini, CEO of Gates MRI, commented that the launch of the trial “demonstrates our commitment to harnessing the power of medical innovation to fight diseases like TB”. These diseases are “particularly devastating for low- and middle-income countries”.
“Clinical study of the vaccine will still require years, but our incredible partners in South Africa and elsewhere who have come together for the Phase III study share our hope in the vaccine’s potential.”
Dr Lee Fairlie, Director of Maternal and Child Health at Wits RHI at University of the Witwatersrand in South Africa, and national principal investigator for South Africa, emphasises that this trial is an “important moment for South Africans” that demonstrates “a strong local and global commitment to fight a disease that remains distressingly common in our communities”.
“South Africa also has considerable experience with TB- and vaccine-related clinical trials and a strong track record for protecting patient safety and generating high quality data essential for regulatory approvals.”
Getting the vaccine to trial
The M72/AS01E vaccine candidate has been in development “since the early 2000s”, originally designed and clinically evaluated by GSK in partnership with Aeras and IAVI. In 2020, GSK announced a partnership with Gates MRI to further develop the vaccine. GSK “continues to provide technical assistance” and supplies the adjuvant component of the vaccine. GSK will provide the adjuvant post licensure if the trial is successful. The trial is sponsored by Gates MRI, with funding from the Gates Foundation and Wellcome.
Gates MRI, GSK, Wellcome, and the Gates Foundation are working together to understand the potential demand for the vaccine and develop an end-to-end plan that ensures long-term sustainable access if the trial is successful. This involves supporting research and building an evidence-base for the potential effect of the vaccine and community requirements for uptake as well as collaborating with multilateral, regional, and country partners to introduce the vaccine. The trial funders also intend to form an international advisory group comprising representatives of these groups to provide input on the programme.
The trial is expected to include up to 20,000 participants, including people living with HIV, across up to 60 trial sites in seven countries: South Africa, Zambia, Malawi, Mozambique, Kenya, Indonesia, and Vietnam. Participants will either receive the investigational M72/AS01E vaccine or placebo in the double-blind trial. The trial is anticipated to last up to 5 years before data analysis and preparation for submission to regulatory authorities.
Deborah Waterhouse, CEO, ViiV Healthcare, and President, Global Health, GSK, is “delighted” that the trial is underway after GSK has dedicated “over 20 years to developing this essential candidate vaccine”.
“Developing and ensuring access to global health products is complex but our collaboration with the Gates MRI, Wellcome, and the Gates Foundation exemplifies the transformative power of leveraging disease partners’ expertise to change the trajectory of challenging diseases, like TB, which place a huge burden on communities around the world.”
Dr Alemnew Dagnew leads the development of the vaccine at Gates MRI and is “particularly excited to see this trial get underway” after experience working as a physician in Ethiopia, which revealed the effect of pulmonary TB on communities.
“If effective M72/AS01E could reinvigorate a global fight against TB that has been weakened by the COVID-19 pandemic.”
Dr Dagnew commented that TB represents both a health and a socioeconomic problem, with the disease primarily affecting people in their “prime” working years, leaving families without income and children without parents. Almost half of TB-affected households face costs higher than 20% of their household income.Dr Trevor Mundel, President, Global Health, Gates Foundation, echoed that the start of the trial is a “pivotal moment” in the fight to “end TB, which devastatingly afflicts the world’s most vulnerable communities”.
“We think this trial marks the beginning of a series of opportunities that will usher in the most promising pipeline ever of new TB tools.”
Dr Mundel stated that the Gates Foundation “remains committed to supporting local and global partners to accelerate the solutions needed to save lives and reduce suffering”. Dr Alex Pym, Wellcome’s Director of Infectious Disease, recognised that there is a “long journey to results”. However, the start of the trial “brings us a critical step closer to having an effective vaccine to protect those most at risk of TB”.
“Global collaboration with regulators, in-country decision makers, and communities affected is crucial if those who need it most are to benefit from this vaccine, should the trial be successful.”
An investigational mRNA vaccine for mpox is being tested in UK with enrolment for healthy volunteers beginning in March 2024. The mPower trial, sponsored by Moderna, is delivered by the NIHR Clinical Research Network (CRN). Although cases of mpox have declined in the UK since a peak that began in 2022, the disease continues to affect people in other countries and “remains a public health threat globally”. There is currently only one vaccine licensed for immunisation against mpox in the UK and Europe, with NIHR claiming “more are needed”.
An urgent need
Dr Rajeka Lazarus, National Co-ordinating Investigator for the study, emphasised that “mpox is a global public health threat” that “urgently” demands “more vaccines”.
“Throughout the COVID-19 pandemic, we were overwhelmed with the generosity of volunteers who came forward to take part in a number of vaccine trials. Without them, the advances we’ve seen would not have been possible. It would be fantastic to see the same support for mpox research.”
Therefore, researchers from University Hospitals Bristol and Weston NHS Foundation Trust are hoping to recruit another 175 volunteers, looking for people who:
Are between 18 and 49 years old
Are in good medical health
Have not been previously vaccinated for mpox or smallpox
Have not had a suspected or confirmed mpox infection
Partnership with Moderna
The mPower Trial is part of the Moderna-UK Strategic Partnership that brings mRNA vaccine manufacturing to the UK and helps the country build resilience to future health emergencies. The 10-year partnership sees Moderna invest a “substantial” amount in research and development. Dr Matthew Hallsworth, NIHR Director of Strategic Partnerships, is “really pleased that Moderna has chosen to run its mpox trial in the UK”, as it “demonstrates our strength in clinical research”.
“Our partnership with Moderna ensures UK research is at the cutting edge of new vaccine technologies with the potential to protect against global health threats such as mpox and future pandemics.”
Dr Hallsworth hopes that the trial recruitment will be “as successful” as COVID-19 vaccine trials and encouraged the UK public to “help out where they can”. This could be “volunteering or encouraging others”.
Personal accounts
NIHR shares two accounts. The first is Harun Tulunay’s story of exposure to the mpox virus. Harun is a sexual health advocate who was exposed in June 2022. At first he thought his symptoms, high fever, shivers, and swollen lymph nodes, were caused by COVID-19 or the flu. However, when a painful blister on his face grew from the size of a spot to covering most of his nose, he became worried. He was referred for an mpox test at a sexual health clinic, but his symptoms worsened before the results came back.
When the lesions in his throat prevented him from eating or drinking, he was admitted to hospital and treated with an antiviral originally developed for smallpox.
“It was an unbearably painful experience.”
Harun used his hospital stay as an opportunity to educate others, documenting the process to spread awareness.
“People didn’t know about mpox. I didn’t know about it. It was really scary, so I started to share my journey…since then, I’ve been an advocate for mpox.”
Harun volunteered for COVID-19 vaccine trials during the pandemic and hopes that others will contribute to this trial too so that vaccination availability will increase both in the UK and abroad.
“As a man living with HIV, I took part in COVID trials and other trials to help other people – people really need to approach this from that perspective. People who participate in this trial will be part of advancing research that will maybe change lives. Being a part of that is such a great feeling – I know that from my own experience.”
The second story is Isabella’s. She is a clinical trials manager from East London and has worked on studies at Queen Mary’s Blizard Institute but never taken part in a trial herself. She heard that the mPower Trial needed healthy volunteers and decided to enrol.
“In pre-COVID days I might have been a bit cautious about clinical trials, even though I work in them myself. There’s something about signing up to receive an injection as a healthy volunteer that is perhaps a barrier and makes you think twice. But I feel like we live in a world where everyone has more scientific awareness and knows a bit more about how vaccines are made – so I felt reassured by that.”
A man who claims to have received more than 200 vaccinations against COVID-19 has been tested by researchers at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen with results published in The Lancet Infectious Diseases. After learning of his remarkable case through newspaper reports the team invited the man to participate in an investigation into the effects of “hypervaccination” on his immune system, finding that it is “fully functional”. However, the researchers emphasise that this strategy is not recommended.
An unusual case
The study reports on a 62-year-old male from Magdeburg, Germany, who “deliberately and for private reasons” received 217 vaccinations against SARS-CoV-2 within 29 months. These vaccinations occurred outside a clinical study context and “against national vaccination recommendations”.
Evidence for 130 vaccinations across a 9-month period was gathered by the public prosecutor in Magdeburg, who opened an investigation into allegations of fraud; however, criminal charges were not filed. 108 vaccinations are individually recorded and partly overlap with the total of 130 prosecutor-confirmed vaccinations.
Called for testing
The researchers were intrigued by reports of this case and submitted an analysis proposal to the man through the public prosecutor. The man “actively and voluntarily consented to provide medical information and donate blood and saliva”. Privatdozent Dr Kilian Schober commented that their volunteer was “very interested” in participating in the study to understand the consequences of such extreme hypervaccination.
Dr Schober explains that for some chronic infections like HIV or Hepatitis B, there is an “indication” that T-cells can “become fatigued” and release “fewer pro-inflammatory messenger substances”. Thus, the immune system is weakened and can’t attack the pathogen effectively.
The study used the results of “various blood tests” over recent years.
“He gave us his permission to assess the results of these analyses. In some cases, samples had been frozen, and we were able to investigate these ourselves. We were also able to take blood samples ourselves when the man received a further vaccination during the study at his own insistence. We were able to use these samples to determine exactly how the immune system reacts to the vaccination.”
The results indicate “large numbers of T-effector cells” against SARS-CoV-2, even more than the control group of participants who had received three vaccinations. Notably, the team did not identify fatigue in these cells; they were “similarly effective” as those in the control group. They also explored the memory T cells, finding that the number was “just as high in our test case as in the control group” according to Katharina Kocher, a lead author.
“Overall, we did not find any indication for a weaker immune response, rather the contrary.”
Alongside the investigations related to SARS-CoV-2, further tests revealed “no change” to the immune system’s effectiveness against other pathogens, suggesting that hypervaccination did not damage the immune system. Dr Schober was particularly intrigued by the variety of vaccines received: a total of eight different vaccines.
“The observations that no noticeable side effects were triggered in spite of this extraordinary hypervaccination indicates that the drugs have a good degree of tolerability.”
Not an endorsed approach
The paper concludes with a reflection that, while the hypervaccination appeared not to harm the man, instead preventing signs of breakthrough infections, the researchers “do not endorse hypervaccination as a strategy to enhance adaptive immunity”.
An article in npj vaccines in February 2024 considers the future of the adult vaccine landscape, using insights from interviews to “serve as a pivotal starting point” to enable industry participants to navigate an “anticipated surge” in “volume and complexity”.
“To unlock the societal benefits of this burgeoning expansion, we need to adopt a fresh perspective to steer through the dynamics sparked by the rapid growth of the global adult vaccine market.”
The authors reflect that vaccine innovation drew “significant attention” during the COVID-19 pandemic but was “already on the cusp of a groundbreaking renaissance”. For adult populations, integration of vaccine programmes is notoriously challenging, suggest the authors, who consider “low uptake, funding shortfalls, and operational hurdles”. Adult immunisation is a key theme for the Congress in Washington, so we explore the article here and invite you to join us in April to share your thoughts on the issue.
At a crossroad
“As the adult vaccine landscape rapidly evolves, we find ourselves at a crossroad where addressing the status quo of immunisation efforts is no longer an option but a necessity.”
The authors state that the COVID-19 pandemic “served as a stark wake-up call”, exposing the “fragmented nature” of adult vaccine infrastructure. The system that was revealed is “wholly unprepared for the impending rapid growth” in adult vaccines. While this may be a daunting situation, the authors believe that these challenges can be “catalysts for transformation”.
The article suggests that the “ongoing and accelerating transformation” in adult vaccines will be “propelled by the rise of RNA technology, thrusting us into a new era of digital vaccine”. Comparing RNA-based solutions with “traditional biologic counterparts”, the authors state that the former are “not constrained by the same production processes”, creating potential to “conceptualise innovative vaccine designs using a single manufacturing process”.
Time for a revolution
“The timing of this vaccine revolution is critical.”
Referring to an ageing global population, the authors identify calls for “more potent vaccines to safeguard health and wellness”. This is emphasised by the effects of vaccine-preventable diseases (VPDs) on the economy; VPDs account for an estimated 8 million to 10 million disease cases in the US alone, which result in “up to $34.9 billion in annual societal costs”. There is an “informal economy” consequence as well, as older adults play an “invaluable role” by offering childcare and financial and emotoinal support, which “cannot be quantified through economic analyses alone”.
However, the development of adult vaccines is not simple; future vaccines must be “tailored to different risk groups” to provide “optimal efficacy”.
Market research
The authors conducted a market research study with the US as a pivotal case study to understand the “evolving” adult vaccine market. From their results they identify challenges and weaknesses that, if neglected, may “quickly become overwhelmed in the face of an evolving and expanding industry”. The goal is to shift the “complacent” implications of the phrase “there is always next year” to an “urgent call for innovation”.
Evolution and growth
Recognising the importance of a paediatric “bias” in the mid-twentieth century, the authors state that the US has a “strong” paediatric immunisation programme with “clear guidelines, well-defined immunisation schedules, and school entry requirements”. However, for adult vaccines there are challenges like “limited awareness, accessibility, affordability, and vaccine hesitancy”.
Despite these challenges, the adult vaccine market is “experiencing rapid expansion” with a growth trajectory driven by increasing prevalence of VPDs in adults, technological advancements, and a “heightened focus” on preventative healthcare.
“Over the next decade, we anticipate a tripling in the number of approved vaccine products globally.”
There are 35 products currently available across 13 disease areas, but over the next 10 years this is predicted to grow to 100-120 risk-adjusted products over 40 different disease areas. Vaccine categories are expected to grow from “well-known diseases” and travel or endemic diseases to include nosocomial vaccines. Furthermore, there is a possibility that vaccines for “high unmet” need diseases like HIV will “enter the adult vaccine landscape”.
Alongside expanded offerings, the authors refer to “growing competition”. Four “historical leaders”, GSK, Merck, Pfizer, and Sanofi, may see “increased pressure” from new entrants and global players.
“Additionally, as best-in-class products likely will not be enough to capture the market, manufacturers are expected to distinguish themselves through differentiated portfolio offerings, rather than individual products.”
As more vaccines enter the market, vaccine schedules are “expected to undergo substantial expansion over the next decade”. Indeed, the phenomenon of “forced seasonality”, where non-seasonal vaccines are administered over a compressed period, could “pave the way for a convergence of campaigns for new vaccines with those of seasonal vaccines”.
“Such alignment could pose substantial challenges for immunisers and vaccination delivery sites as they grapple with the task of accommodating new patients and vaccines within a more limited timeframe.”
Breaking down barriers
The authors conducted a market research study of both qualitative and quantitative approaches to understand the “potential challenges and reactions to future states of the adult vaccine landscape”.
“Through interviewing and surveying key adult vaccine market stakeholders, we found that many stakeholders may not be fully cognisant of the impending wave of adult vaccines.”
This ignorance is largely attributed to an “absence of incentives to assess situations beyond the current fiscal year”, which then fosters “short-term thinking” and hingers the identification of “potential long-term effects” within the market. This could lead to “lack of preparation” and result in “missed opportunities”.
“The adult vaccine market has also seen a shift in focus to newer participants, such as the rise of alternative vaccination sites like pharmacies, aiding a decades long trend, which is expected to continue.”
While this change brings opportunities, it also presents challenges, such as “concerns” about pharmacists’ access to medical records and vaccination histories. To address this, the authors state that we need to build a “sense of trust” between pharmacists and physicians, which will be “paramount to the successful dissemination of future vaccines”.
Another consideration is the experience of a pandemic and how it may distort perceptions for the future; the authors emphasise the importance of remembering difficulties in distribution and looking forward to a “dynamic environment” that will demand “continued vigilance, flexibility, and readiness to embrace change”.
The adult population
Another challenge arises in considering the intended recipients of these vaccines. For example, patients were willing to receive “up to four” vaccines a year but preferred to limit administration to two per visit: one in each arm.
“The expansion of the adult vaccine market means that consumers will need to take more ownership of their vaccination schedules and records.”
Even if patients are keen to access vaccination programmes, the authors consider that “far too many in the US still suffer from unequal access to healthcare”. Disparities cause a divide in “actual health outcomes”. However, they recognise that apart from the “moral imperative” of “bridging the equity gap” there is a financial incentive: estimates suggest that eliminating racial disparities alone could save “over $90 billion” annually in “unnecessary medical expenses”.
“Unfortunately, our market research has highlighted that no stakeholder group is individually accountable for addressing vaccine equity. We found a significant gap in understanding and responsibility within the vaccine ecosystem, leading to a disconcerting reality: equity is falling through the cracks.”
What do the authors conclude?
“The adult vaccine market stands on the threshold of significant growth in the forthcoming years. Preparing to incorporate more vaccine into the existing ecosystem could lead to enhanced health and economic outcomes in the future.”
The article recommends “proactive solutions” that consider the “consumer and their choices”. What might this look like in your work? Do you agree with any of the arguments or findings in the article? We look forward to considering adult immunisations in greater detail during the Congress; are you joining us there? Don’t forget to subscribe for weekly insights.
A paper in Nature microbiology in February 2024 presents the results of investigations into whether human genetic variation “underlies the heterogeneity” of Lassa fever, caused by infection with Lassa virus. Among the techniques used, the researchers carried out genome-wide association studies (GWAS) to demonstrate how GWAS can “provide insight into viral pathogenesis”. They were able to identify variants and genes that may influence the risk of severe Lassa fever.
Lassa: a substantial threat
WHO describes Lassa fever as an “acute viral haemorrhagic” illness that can result from infection with Lassa virus (LASV), initially causing fever symptoms and sometimes progressing quickly to respiratory distress, mucosal bleeding, shock, and multiorgan failure. Although “about 80% of people” who become infected with LASV present no symptoms, 1 in 5 infections results in “severe disease”.
The authors suggest that overall case fatality rates (CFRs) can be as high as 29.7% in laboratory-confirmed patients and over 50% in foetuses.
“This lethality, coupled with the aerosol-based route of exposure and lack of approved therapeutics or vaccines, means that LASV is a World Health Organisation risk group 4 pathogen, biosafety level 4 (BSL-4) agent, and substantial threat to public health.”
The virus is “ubiquitous” in “many regions of West Africa”. The main host and reservoir of LASV is the Mastomys natalensis, a rodent that lives “near houses in rural villages”. Transmission to humans occurs through “aerosolization of viral particles” from rodent excrement. Person-to-person transmission “usually only” occurs in nosocomial settings, but the prevalence and transmissibility of LASV lead to an estimated 100,000-300,000 infections annually.
Variability
Despite high prevalence, “only hundreds to thousands” of cases of Lassa fever are diagnosed each year, which implies that most infections are undocumented and mild. It is not clear why severe disease and death only occurs in some infections. While old age and pregnancy are associated with “poor” outcomes, they do not explain all the variability in infection outcome, and variability in LASV lineages “has not been linked to severity of symptoms”.
The authors propose that human genetic variation may contribute to outcome variability for LASV infection, reflecting that host genetics has been linked to symptoms caused by infection with SARS-CoV-2, HIV, and dengue, among others.
“The link between host genetics and LASV infection is intriguing because LASV may have been an important selective force in endemic regions, driving variants that protect against Lassa fever to higher prevalence.”
Indeed, previous research identified a signal of positive selection in a Yoruba population in Nigeria, who live in a LASV endemic region at a locus overlapping the gene LARGE1. LARGE1 “encodes a protein that glycosylates α-dystroglycan, the primary cellular receptor for LASV.
“Given Lassa fever’s lethality among diagnosed cases and the high seroprevalence to LASV, it is plausible that host variants providing resistance might have an impact on reproductive fitness.”
Furthermore, phylogenetic dating suggests that LASV has been in Nigeria for over 1,000, which allows for the possibility that the virus has “exerted evolutionary pressure” on humans. However, no previous studies have systematically assessed the relation between host variation and LASV infection.
There are “practical obstacles” to studying Lassa fever in humans that the authors identify:
LASV is a BSL-4 pathogen endemic in countries that have only recently obtained infrastructure for safe virus handling.
Medical infrastructure is lacking in the villages where Lassa fever is most common, so most symptomatic cases are undocumented.
Genetic diversity of LASV isolates means that diagnostics based on nucleic acid amplification or immunoassays can have low sensitivity. Without FDA-approved LASV diagnostics, proven diagnoses require viral culture, which is generally unfeasible.
The team behind the paper “anticipated that it would be challenging to obtain a sizeable enough cohort” for a Lassa fever genome-wide association study (GWAS) but considered that “increased power would arise if natural selection for resistance to Lassa fever was present”.
Preparations began in 2008, establishing public health and research capabilities for Lassa fever in Nigeria and Sierra Leone. Patients with Lassa fever were recruited and genotyped and matched with individuals who do not have LASV symptoms during a 7-year period from LASV endemic regions. Genome-wide association with Lassa fever susceptibility and fatal outcomes was tested, with sub-analyses to specifically consider variation at LARGE1 and human leukocyte antigen (HLA) loci.
GWAS for a group 4 pathogen
The “first GWAS of infection with a risk group 4 pathogen reported to date” was conducted over 10 years. It found that an intronic variant within GRM7 and a variant downstream of LIF are “significantly associated” with Lassa fever in the Nigeria cohorts and meta-analysis of the two cohorts respectively and identified candidate variants that approach, but do not reach, genome-wide significance in susceptibility analyses.
LIF encodes an interleukin 6 family cytokine that “could impact Lassa fever severity”. GRM7 “may function in viral entry akin to GRM2 in in coronavirus disease 2019” or “could be involved in immune activation”. Furthermore, GRM7 is involved in maintenance of hearing by inner-ear hair cells, and hearing loss is a “notable symptom” of Lassa fever.
The team also used their data to examine the hypothesis that positive selection for genetic variation at the LARGE1 locus provides protection, finding that a haplotype with long-range LD, indicative of recent positive selection, is “nominally associated with reduced likelihood” of Lassa fever in the Nigeria cohort but not in the Sierra Leone cohort.
“Larger cohorts and deeper phenotypic characterisation will be required to evaluate the hypothesis of LARGE1 mediated genetic resistance to Lassa fever susceptibility.”
Recognising the limitations of their study, the authors call for “continuing efforts” to improve understanding of genetic variation in African populations to provide more insight into the potential links between genetics and disease.
“Our work paves the way for follow-up studies on Lassa fever and other group 4 microbial pathogens and has contributed to an improved genetic data resource for African populations.”
An article for BMJ Global Health in January 2024 states the importance of moving in the direction of “global vaccine equity with shared goals, intermediate steps, and long-term advocacy goals”, with an emphasis on doing so “before the next pandemic”. Recognising that “vaccines are key to preventing and ending pandemics”, the authors state that COVID-19 “will not be the last pandemic” and invite countries to use lessons from their experience of it, as well as their responses to the HIV pandemics. They describe the HIV response as “at the vanguard of ensuring equitable access to rights-based services, to create shared goals and engage communities to increase access to and delivery of safe, quality vaccines”.
COVID-19 and inequality
Even though COVID-19 is known to have been a “leading cause” of morbidity and mortality globally, resulting in “almost 7 million deaths” by January 2023, many cases were undetected due to “widespread lack of diagnostic test availability”. Therefore, the human burden is underestimated. Although vaccines have “been essential” in reducing this burden, countries “scrambled” to access them, which meant that “the most effective vaccines largely went to countries in the Global North” at the start.
For example, the Africa region represents one-fifth of the global population but had only received 3% of all COVID-19 doses by 2021.
“While the number and types of vaccines delivered to the Global South have increased over time, countries in the Global South have been the most disadvantaged in obtaining access to the most effective vaccines.”
Vaccine equity
The authors consider “two central dimensions” for vaccine equity:
Access – are the vaccines a country has the most effective vaccines available? Are the prices for the vaccines affordable for the country?
Delivery – Does the country have a quality healthcare system, supply chain, and workforce to deliver the vaccines?
Even within countries, vaccines have been distributed “unequally”, usually to the disadvantage of the most vulnerable, including “people with disabilities, homeless populations, refugees, as well as those in prisons, crowded living conditions, and with precarious work conditions”. Furthermore, those living with HIV who are not virally suppressed are at “high risk” of COVID mortality. The article highlights that of the 38 million people who live with HIV, more than 25 million live in Africa, which has the lowest rates of COVID vaccination.
“While public health dictates that those at highest risk should be the highest priority to be vaccinated, one reason this did not occur is that individuals who had resources or were in positions of power were vaccinated first.”
This persists, despite recognition that, to limit mutations and further spread, we need to vaccinate a global majority. Therefore, the authors distil policy-level recommendations and actions for consideration by Global South country leaders.
“Given how little progress has been made to date, in an effort to ‘decolonise’ global health, countries in the Global South and CSOs may want to consider what actions to take now that will not solely depend on the goodwill of the Global North.”
Increasing access
Decentralise the production of vaccines, fostering the increased production of mRNA vaccines on many continents rather than relying on donations. The authors call for the development of a “transparent, web-based system” to monitor the supply chain that supports vaccine developers and manufacturers. They highlight that donations from the Global North are a “short-term, not perfect solution” that perpetuates dependency on donors.
Create a system of price transparency for vaccines. For example, COVAX is a public-private partnership founded to deliver COVID vaccines globally, but it did “not meaningfully” engage countries in the Global South or CSOs.
“Transparency of pricing could be a way to obtain the lowest price for low-income countries in the Global South, following the model established by UNICEF for childhood vaccines.”
Collect easily understandable, accessible, and transparent data on COVID vaccines. The authors suggest a website with the following information:
What is the effectiveness of different vaccines against which variant to prevent mortality?
Where are the different vaccines available?
Where is a particular vaccine useful given a country’s infrastructure?
Safety profile of the different vaccines
Cost per dose of vaccine in each country
Create demand for a new international legal framework that allows intellectual property (IP) rights to be waived quickly once a global pandemic is identified. Although the most effective vaccines with the fewest side effects were the mRNA vaccines developed by Pfizer and Moderna, US law “encourages grantees to protect their findings as IP”, to be sold to pharmaceutical companies which are unlikely to undertake development without profit guarantee.
“An ongoing global advocacy strategy by Global South governments, CSOs, and multilateral and bilateral organisations pressuring the Global North to engage in improved global vaccine equity is needed.”
A model for this could be based on HIV-focused efforts, as the authors highlight that the AIDS pandemic showed that “public advocacy leads to results”.
“We recommend that countries work simultaneously to both build their own mRNA vaccine production, supply, and expertise, as well as negotiating with pharmaceutical companies.”
Draw on the expertise of scientists in pharmaceutical companies around the world and other expert scientists globally who are willing to share and collaborate. Although mRNA vaccines are “new technology”, and access to this kind of expertise is “challenging”, the authors refer to Afrigen scientists receiving training and a US-South Africa-Thailand partnership to conduct manufacturing in line with GMP and share other scientific information.
Improving delivery
Create or strengthen public health systems that can deliver vaccines and other healthcare services throughout the lifespan that will lead to a reduction in morbidity and mortality.
“There is an ongoing need to create an adequate cadre of health workers, with sufficient remuneration and with the resources needed to succeed.”
Furthermore, specific laws might be required to protect healthcare workers and ensure fair working conditions. Donors can get involved by investing in “creating community demand and decision-making”. A “practical goal” for pandemic preparedness is the 7-1-7 target for detection, notification, and response: this allows primary care 7 days to assess a suspected outbreak, 1 day to notify public health authorities, and 7 days to implement effective responses.
Vaccinate strategically, vaccinating as many as possible, particularly those at highest risk, with available vaccines to reduce mortality. The authors highlight Vietnam’s use of non-pharmaceutical interventions in advance of vaccination campaigns and “massive diffusion of all media” until the country had access to vaccines.
Based on public health criteria, create an equitable system of prioritisation for gaining access to vaccines. The healthcare workers and providers must be “among the first to gain access” to lifesaving vaccines in a “functional” health system.
We recommend to either create and/or strengthen national regulatory agencies (NRAs) to appropriately regulate vaccines, ensuring that any manufacturing of vaccines meets GMP standards. Countries need transparent and effective NRAs, and where they do not have their own, they can “draw on regional regulatory systems” such as the Caribbean Regulatory System.
Identify credible, trusted sources of health information, promote health literacy and create a national scientific advisory committee to disseminate accurate and reliable information during a pandemic. Improved health literacy encourages an understanding of changing guidance in response to emerging data. All platforms that can be “interactive, trusted, and transparent” should be used and balanced with the “needs and concerns of the population”.
Foster transparent surveillance systems. Improving birth and death registrations and sharing these data can inform accurate pandemic information.
Conclusions
“A number of the interventions suggested as a way forward to move towards global vaccine equity may take varying lengths of time to institute, so therefore, it is critical to start now to take action for the future.”
The authors state that from a “moral ethical” position and the view of “reducing preventable mortality globally”, it is important that vaccine equity is a goal with “practical intermediate steps and long-term advocacy goals”.
“Scientific integrity, transparency, accountability, and clear communication will be key.”
How do you think these recommendations could be effectively implemented both in the immediate future and as we try to make pandemic preparedness a more established approach? Many of the issues that are explored throughout the paper will be considered at our Congress in Washington this April; are you joining us there? Until then, don’t forget to subscribe for more global health insights!
