by Charlotte Kilpatrick | Aug 19, 2024 | Technology |
In August 2024 Tonix Pharmaceuticals “reiterated its commitment” to advancing the development of its live attenuated virus vaccine TNX-801 for the prevention of mpox and other infectious diseases. This comes after WHO declared that the spread of mpox in Africa represents a public health emergency of international concern. TNX-801 is a live replicating attenuated vaccine candidate, based on horsepox, and is believed to provide protection with “better tolerability” than 20th century vaccinia viruses.
TNX-801
The platform behind TNX-801 was chosen by US NIH for Project NextGen efforts against SARS-CoV-2 but has also protected animals against lethal challenge with intratracheal Clade 1 monkeypox virus. Tonix states that the recombinant horsepox virus vaccine uses a live replicating, attenuated virus that has “been shown to be >1,000-fold more attenuated than 20th century vaccinia” (VACV) strains in immunocompromised mice. The virus can be engineered to express foreign genes and is a strong platform for vaccine development because they have:
- Large packaging capacity for exogenous DNA inserts
- Precise virus-specific control of exogenous gene insert expression
- Lack of persistence or genomic integration in the host
- Strong immunogenicity as a vaccine
- The ability to rapidly generate vector/insert constructs
- Potential to be readily manufacturable at scale
- The ability to provide direct antigen presentation
Although Tonix’s current formulation is a frozen liquid, the team indicates that future lyophilised versions could be stored and shipped at standard refrigeration.
“Horsepox-based vaccines are designed to be single dose, vial-sparing vaccines that can be administered without sterile injection, manufactured using conventional cell culture systems with the potential for mass scale production, and packaged in multi-dose vials.”
A need for accelerated efforts
Dr Seth Lederman, Chief Executive Officer of Tonix, recognises that the WHO declaration “underscores the urgent need for additional treatments to stop these outbreaks and save lives”.
“We are motivated to advance development for our mpox vaccine with urgency given the global public health emergency.”
Dr Lederman states that TNX-801 “combines immune protection with improved tolerability and safety” and has the advantage of a single dose administration.
“Also, the stability of live virus vaccines eliminates the need for ultra-cold storage which complicates the widespread use of mRNA vaccines in Africa, where they are needed most right now.”
We look forward to hearing more about Tonix’s mpox vaccine development at the Congress in Barcelona this October. To join us get your tickets here, and don’t forget to subscribe to our weekly newsletters for vaccine updates.
by Charlotte Kilpatrick | Aug 19, 2024 | Technology |
A study by researchers at Yale School of Medicine (YSM), Northeastern University, and Rice University in Science (not open access) in August 2024 presents new views of an “intricate molecular dance” between human cells and SARS-CoV-2. Their findings could allow more effective vaccine development as variants emerge. The authors used cry-electron tomography to capture intermediates of the S2 domain “refolding” and to understand inhibition by antibodies to the S2 stem-helix. They hope that their research provides insights into the process of SARS-CoV-2 entry and reveals how pan-betacoronavirus S2-targeting antibodies neutralise infectivity by “arresting prehairpin intermediates”.
Spike protein
YSM states that the viral spike protein comprises two parts: one binds the human protein ACE2, on the surface of many cells, and the other adapts its shape to bring the virus closer to the cell after it is attached. This proximity enables the membranes of the virus and cell to fuse, allowing the virus to enter the cell. Current COVID-19 vaccines were designed to include the ACE2-binding element of the spike protein; this is “prone to pick up mutations as the virus evolves”. Keeping up with these mutations, even with annual updates”, would be impossible.
“A different potential target of opportunity – the shape-changing part of the protein – is very unlikely to mutate, because its structure is so critical for narrowing the gap between virus and cell.”
Vaccines that target this “stable structure” could be “universally effective” against more dangerous variants, and even other coronaviruses.
Cutting-edge technology
The scientists used virus-like particles coated with either the spike protein or ACE2 to simulate binding. With a microscopy technique, cryogenic electron tomography (cryo-ET), they imaged this interaction to capture “detailed 3D structures”. Next, the teams at Northeastern and Rice used this data to develop computational simulations of the process. This research allowed the teams to view the spike-ACE2 interaction and subsequent fusion intermediates that had previously not been seen to such a high level of detail.
A key revelation was in the details of the spike protein’s “dramatic shape change”, which PhD researcher and first author Michael Grunst likens to a “jackknife folding shut”. Dr Wenwei Li, associate research scientist, was excited to see the structure of the “intermediate stages”.
“We found that this region is even more dynamic than what we thought before.”
The researchers also captured images of the two proteins together, with antibodies that bind to the “shape-changing region”. Their simulations revealed that the antibody blocks the spike protein from “folding in on itself”, thus preventing it from bringing the virus and cell membranes together for fusion. Grunst highlights the implications of this for vaccine development as the virus mutates rapidly.
“Understanding how these antibodies work to block the fusion machine can help understand how to better design immunogens.”
They also showed that antibodies bind to a “transient folded form” of the spike protein, which could explain why these antibodies are quite rare; the immune system is only exposed to the specific shape for a “short window of time”. Dr Walter Mothes, Paul B. Beeson Professor of Medicine at YSM, states that these details could help vaccine developers select the right part of the virus to simulate the production of more antibodies.
“COVID variants can escape our immune systems and vaccines by mutating, but these fusion machines have only one pattern of how to do their job. It’s a hardwired, conserved machine; you can’t change them. So this is why understanding more about how that mechanism works means we can learn more about their vulnerability.”
For more on the next generation of COVID-19 vaccines and innovative approaches to addressing future variants, why not join us at the Congress in Barcelona this October? Don’t forget to subscribe to our weekly newsletters here for more vaccine updates.
by Charlotte Kilpatrick | Aug 14, 2024 | Technology |
The Indian Council of Medical Research (ICMR) and Panacea Biotec announced in August 2024 that they have initiated the “first-ever” Phase III clinical trial for a dengue vaccine in India. The trial will evaluate the efficacy of Panacea Biotec’s tetravalent dengue vaccine, DengiAll. The first participant in the trial was vaccinated at Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences (PGIMS), Rohtak. Although there is no antiviral treatment or licensed vaccine against dengue in India, the development of an effective vaccine is “complex” as good efficacy must be achieved across four serotypes.
Dengue in India
Dengue is described as a “major public health concern” in India, and global incidence has been “steadily increasing” over recent decades. Around 75%-80% of infections in India are asymptomatic, but this does not prevent further transmission. Among the remaining cases that present with “clinically apparent” symptoms, children are at a greater risk of hospitalisation and mortality. Dengue virus has four serotypes, but these have low cross-protection against each other, which means that individuals can suffer repeated infections. All four serotypes are known to circulate or co-circulate in “many regions” of India.
DengiAll
DengiAll is a lyophilised tetravalent live-attenuated dengue vaccine developed by Panacea Biotec in collaboration with the US National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). It is a single dose subcutaneous vaccine, “analogous to NIH Tetravalent Vaccine”, which has been evaluated in “numerous” Phase I & II trials in the US to demonstrate an “acceptable” safety profile and “robust” responses.
Panacea Biotec was one of three Indian companies to receive the vaccine strain and has achieved the “most advanced stage” with this strain. In collaboration with ICMR, Panacea Biotec is conducting the Phase III clinical trial at 19 sites in 18 States and Union Territories. The trial will involve more than 10,335 healthy adult participants; it is primarily funded by ICMR with partial support from Panacea Biotec.
Union Minister of Health and Family Welfare, Shri J.P. Nadda commented that the initiation of the trial for “India’s first indigenous dengue vaccine marks a critical advancement” in the fight against dengue.
“It reflects our commitment to protecting our citizens from this pervasive disease and underscores India’s capabilities in vaccine research and development. Through this collaboration between ICMR and Panacea Biotec, we are not only taking a step towards ensuring the health and well-being of our people, but also reinforcing our vision of Atmanirbhar Bharat in the healthcare sector.”
Atmanirbhar Bharat, or “self-reliant India” is an effort to “make the country and its citizens independent and self-reliant in all senses”.
For more on vaccine trial developments at the Congress in Barcelona this October, get your tickets to join us here. Don’t forget to subscribe to our weekly newsletters here.
by Charlotte Kilpatrick | Aug 13, 2024 | Technology |
In August 2024 Pfizer announced positive top-line safety and immunogenicity results from substudy B of its ongoing Phase III clinical trial MONeT (RSV IMmunisatiON study for adulTs at higher risk of severe illness). The trial evaluates two doses of the ABRYSVO vaccine in immunocompromised adults aged 18 and older who are at risk of developing severe respiratory syncytial virus (RSV)-associated lower respiratory tract disease (LRTD). Pfizer states that the results “add to the growing body of evidence” suggesting that a single dose of the vaccine provides “strong immune protection against outcomes caused by RSV”.
The study
Adults who have immunocomprising conditions are at increased risk of developing RSV-LRTD. The substudy of the MONeT trial was designed to assess the safety and immunogenicity of two doses of ABRYSVO, administered one month apart, in four groups of immunocompromised adults:
- Those with non-small cell lung cancer
- Those on haemodialysis due to end-stage renal disease
- Those with autoimmune inflammatory disorder receiving active immunomodulator therapy
- Solid organ transplant recipients
203 adults were enrolled in the open-label study; approximately half were aged 18 to 59 and approximately half were 60 years or older.
ABRYSVO was “well-tolerated” in the trial, showing a safety profile “consistent with findings from other studies of the vaccine”. Although two doses were evaluated, a single 120 µg dose of ABRYSVO generated a “strong” neutralising response against both subtypes of RSV, RSV-A and RSV-B, in all cohorts and age groups in the study.
Encouraging data
Dr Annaliesa Anderson, Senior Vice President and Chief Scientific Officer, Vaccine Research and Development, Pfizer, highlighted that immunocompromised adults, such as patients with cancer or autoimmune disorders, have a “substantially increased risk of experiencing severe complications from RSV”. However, there are “currently no vaccines approved for those aged 18 to 59 in the US”.
“We are encouraged by the positive top-line data from this study, which provide important evidence that ABRYSVO has the potential to address a significant unmet need in this vulnerable population.”
For more on efforts to limit the damage caused by RSV in a range of subpopulations, join us at the Congress in Barcelona this October, and don’t forget to subscribe to our weekly newsletters here.
by Charlotte Kilpatrick | Aug 12, 2024 | Technology |
An article in npj vaccines in August 2024 presents research into the efficacy of a deactivated rabies virus (RABV)-based vaccine encoding the glycoprotein precursor (GPC) of Lassa fever virus (LASV): LASSARAB. In nonhuman primates (NHPs), the vaccine induced “strong” humoral responses and NHPs that had been vaccinated with LASSARAB survived to study endpoint after challenge. The authors state that their work demonstrates that LASSARAB is a “worthy candidate for continued development”.
Lassa fever virus
Lassa fever virus (LASV) is an emerging biosafety level-4 (BSL-4) haemorrhagic virus with no approved vaccine. Endemic to West Africa, the virus is maintained by a rodent reservoir, Mastomys natalensis, and is commonly transmitted to humans who come into proximity with infected rodents. Human-to-human transmission also occurs, most frequently in nosocomial settings. An estimated 300,000-500,000 people are infected with LASV each year, and the overall case fatality rate (CFR) is 1%-2%. However, this increases “significantly” for hospitalised patients.
Lassa fever (LF) is likened to other haemorrhagic fevers; it starts with flu-like symptoms, such as fever, sore throat, and headache. In severe cases it can progress to vascular leakage and multiple organ failure. Although many patients survive, some develop severe sequelae, such as sensorineural hearing loss. LASV is a high-priority pathogen.
Vaccine development
LASV has a bi-segmented, abisense RNA genome that codes for four proteins. The glycoprotein precursor (GPC) is proteolytically cleaved by a host protease into two glycoproteins (GP1 and GP2). These are present on the surface of the virion and are “used for attachment and entry into cells”.
The researchers identified the GPC gene as an “attractive target” for LASV vaccine development because of the “easy accessibility of the glycoproteins to the immune system” and the gene’s “indispensable function in the LASV lifecycle”. Although vaccine candidates targeting GPC were protective in challenge models, they have “disadvantages”. For example, DNA vaccines are “poorly immunogenic without the use of speciality delivery techniques” like electroporation. RNA-based vaccines require cold-chain storage, and live viral vectors can develop mutations.
“The need for the development of alternative vaccine strategies that mitigate these issues remains.”
Rabies virus (RABV) is a “promising” vaccine platform that has already been used with success as a platform for various pathogens. It is administered as an inactivated vaccine, has a “well-established” safety profile, and offers long-term protective immune responses to the rabies antigens. RABV also shared endemic regions with many pathogens, including LASV. Finally, an inactivated RABV vectored vaccine can by lyophilised and remains stable at various temperatures.
“The RABV platform is an excellent choice for a LASV vaccine.”
Previous research has indicated that vaccine-mediated protection against LASV can occur through “various mechanisms”, but a commonality between platforms is a poor neutralising antibody response after vaccination. However, the authors are unsurprised by this, given the “absence” of neutralising antibodies seen in many convalescent LASV patients.
When LASSARAB was administered to NHPs it elicited strong antibody responses to LASV-GPC and RABV glycoprotein (G) for “up to a year” post immunisation. Following this, the researchers sought to test the efficacy of LASSARAB in a lethal LASV NHP challenge model. They immunised NHPs with LASSARAB or CORAVAX (an irrelevant RABV-based vaccine) as a negative control. The NHPs were challenged with LASV at day 70 post immunisation.
The study
The article reveals that no neutralising antibodies were detected in LASSARAB vaccinated NHPs before day 10 post challenge (pc). After detection at day 10 pc, neutralising antibody titres peaked between days 14 and 21 pc and persisted at “varying levels” to day 28 pc in all LASSARAB vaccinates. This suggests that neutralising antibodies are produced as a result of LASV challenge, rather than vaccination with LASSARAB, therefore “not playing a main role” in vaccine-mediated protection.
All LASSARAB-immunised NHPs survived challenge; only one NHP demonstrated “minor outward clinical signs and four NHPs showed transient viraemia. LASV infection has a significant effect on the liver, revealed by a “dramatic increase in liver enzymes”. However, LASSARAB-immunised NHPs maintained normal blood chemistry levels compared to controls; this indicates protection from liver dysfunction.
Despite the “positive clinical outcome” and lack of CBC and blood chemistry changes in vaccinated NHPS, pathologic analysis revealed “significant lesions” in lymphoid tissue as well as smooth muscle layer of arteries in multiple organ systems that stained positive for LASV antigen. This resembles a systemic auto-immune vasculitis, described in NHPs and guinea pigs that survive LASV infection.
LASV in NHPs has a “somewhat protracted” disease process compared to other haemorrhagic fever viruses. The study endpoint was 28 days after virus exposure, but the authors acknowledge that “it is unknown” if the pathology observed in vaccinated survivors at day 28 would have resolved or become less prevalent with a longer endpoint. They suggest that studies with longer endpoints are necessary to determine if the severity of polyarteritis in the LASSARAB vaccinated NHPs resolves over time or can be avoided with administration to a “more mature cohort” of NHPs. Studies will also be required to verify that this pathology was not caused by the vaccine itself.
The protective efficacy of LASSARAB is “comparable” to other vaccine platforms, with 100% of LASSARAB-vaccinated NHPs surviving challenge and presenting “minimal” clinical signs. However, the inactivated RABV platform has “some advantages”. The rabies vaccine has been used for decades and is “safe to administer to a variety of patient populations”. It has been shown to elicit long-term immunity in humans, and “appears to confer this longevity to foreign antigens”.
Another advantage of the RABV platform is that it has been shown to remain stable over a variety of temperatures for “extended periods of time”. This is particularly pertinent for areas in which LASV is endemic, as they have “warm climates and limited access to cold-chain storage”. It is also already commercially available, so there is existing infrastructure for production.
Further research needed
The authors state that they are setting up a Phase I clinical trial of LASSARAB in the US but highlight that other studies should be performed to support its use in the clinic. Although the vaccine has potential for cross-protection, further studies should investigate this. Research should also determine whether LASSARAB can protect NHPs after single-dose immunisation, and how soon after immunisation it confers protection.
We look forward to hearing more about a Lassa fever vaccine candidate at the Congress in Barcelona this October and exploring priority pathogens with our experts. Get your tickets to join us there, and don’t forget to subscribe to our weekly newsletters here.
by Charlotte Kilpatrick | Aug 9, 2024 | Technology |
CEPI announced in August 2024 that it is providing a $5 million cash injection to Boost Biopharma to advance its “cutting-edge” rapid antigen design process. This has potential to enable faster development of safe and effective vaccines, supporting CEPI’s 100 Days Mission efforts. Boost develops recombinant protein vaccine candidates like a COVID-19 vaccine; the latest funding will contribute to a Phase I clinical trial in collaboration with the US NIH and NIAID.
A specialised antigen
The team at Boost has been working on a specialised protein antigen since 2020. This is built with a molecule that improves stability and has the potential to enhance immune responses. With more a more specialised antigen target, vaccines could be safer and more potent, reducing the need for adjuvants. Boost’s antigen construct is also stable at high temperatures, which can improve distribution, and is easily purified, which can accelerate manufacturing and reduce costs.
The trial
The Phase I trial will assess the vaccine, delivered through injection or nasal mist. Nasal mist administration offers an “additional layer of protection”, which is believed to have potential in stopping onward transmission of airborne respiratory viruses. Immunogenicity studies have already been conducted with the support of NIAID’s Preclinical Services Division, demonstrating the vaccine’s “strong performance” in comparison with an mRNA vaccine. In line with CEPI’s Equitable Access Policy both organisations’ commitment to enable equitable access to outputs of the partnerships, results from this research will be published in open access journals.
A potential gamechanger
Dr In-Kyu Yoon, Executive Director of Vaccine Research and Development (Acting) at CEPI, reflects that, although COVID-19 vaccines have protected “millions of lives” across the world, we have “constantly been one step behind”. The “Greek alphabet salad of different variants and subvariants” continues to evade the available tools.
“Being able to quickly update protein vaccines against fast-emerging viral mutations at pace with mRNA vaccines has the potential to be a gamechanger when faced with future COVID-19 variants or another evolving threat, as protein vaccines are currently cheaper to produce or more stable, which could help them get to more people worldwide.”
Boost co-founder and CEO, Dr Steve Gold, is “incredibly pleased to have CEPI’s support” as the organisation makes the transition from preclinical development to first human clinical trials. The funding is a “wonderful validation” of the team’s efforts and technology, but also provides a “clear pathway into the clinic” for the vaccines.
“We hope that safety and efficacy will be fully demonstrated so that our vaccines will ultimately be approved and made available to help millions of people around the world. It has been a pleasure to get to know the dedicated and experienced team at CEPI, and we are excited to move forward together.”
We look forward to welcoming senior representatives of CEPI back to the Congress in Barcelona this October and are delighted to see this positive development for one of our start-ups, Boost Biopharma. To engage with key industry players do get your tickets to join us in Barcelona here, and don’t forget to subscribe to our weekly newsletters here.
by Charlotte Kilpatrick | Aug 8, 2024 | Technology |
Bavarian Nordic announced in August 2024 that the US Biomedical Advanced Research and Development Authority (BARDA), part of the Administration for Strategic Preparedness and Respond in the Department of Health and Human Services, has placed an order valued at US$156.8 million. The order concerns additional bulk product for the company’s smallpox/mpox vaccine, JYNNEOS. The bulk product represents $139.7 million of the contract value and will be manufactured and invoiced in 2024. This will “partly replenish” the inventory used to manufacture vaccines in response to the mpox outbreak in 2022. Around $17 million in the contract covers “additional services” in the 2025-2027 period, including storage of vaccine doses in the US.
MVA-BN
Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) is a non-replicating smallpox and mpox vaccine that has been approved by the FDA, EC, Health Canada, MHRA, and Swissmedic. It also obtained emergency use authorisation in other areas for use in the mpox outbreak.
Preparedness efforts
To fulfil the company’s existing contract to supply a next-generation, freeze-dried version of the vaccine for US smallpox preparedness, the bulk inventory must be replenished. Bavarian Nordic’s President and CEO, Dr Paul Chaplin describes the smallpox/mpox vaccine as a “key component” in the US biological preparedness, which was demonstrated in the 2022 mpox outbreak.
“JYNNEOS was also the first smallpox vaccine successfully developed under Project BioShield, a programme created by the US Congress in 2004 to accelerate the research, development, procurement, and availability of medical countermeasures against biological, chemical, radiological, and nuclear (CBRN) agents through public-private partnerships.”
Dr Chaplin is “proud” to continue providing vaccines to protect US citizens against “current and future public health threats”.
“We applaud the US government’s steadfast commitment to maintaining a robust preparedness.”
A longstanding relationship
Bavarian Nordic states that it has worked with the US since 2003 on the development, manufacturing, and supply of a non-replicating smallpox vaccine. Before the vaccine was approved by the FDA in 2019, Bavarian Nordic had supplied nearly 30 million doses of the liquid-frozen version; most of these were delivered for emergency use and have now expired. BARDA supported the development of a freeze-dried version with a longer shelf-life.
We look forward to welcoming Bavarian Nordic as Diamond Sponsors to the Congress in Washington in 2025. Get your tickets to hear from and network with senior representatives there, and don’t forget to subscribe to our weekly newsletters.
by Charlotte Kilpatrick | Aug 8, 2024 | Technology |
Researchers in Science Advances present their work developing a “highly modular saponin-based nanoparticle platform”. The platform incorporates Toll-like receptor agonists (TLRas), including TLR1/2a, TLR4a, and TLR7/8a adjuvants and their mixtures. These induce “unique acute cytokine and immune-signalling profiles”, which facilitate specific T helper responses. In a murine vaccine, study the adjuvants “greatly improved” the potency, durability, breadth, and neutralisation of COVID-19 and HIV vaccine candidates. The authors believe their work highlights the potential of a modular TLRa-SNP adjuvant platform for improving vaccine design.
Adjuvant demands
Although prophylactic vaccine development has been “at the heart of intensive scientific research for the past hundred years”, the authors suggest that the emergence of global pandemics has “catalysed their development”. However, “many” commercial vaccines have “complex manufacturing processes and potential safety hazards”. Protein-based subunit vaccines offer “desirable” safety, cost-effectiveness, scalability, and manufacturability characteristics. They leverage adjuvants to promote the “magnitude and durability” of the immune response.
Although “only a handful” of adjuvants are clinically licensed in vaccine formulations, the authors identify potential in Toll-like receptor agonists (TLRas). These differ in physical and chemical properties but activate different Toll-like receptors (TLRs) commonly expressed by antigen-presenting cells to “drive distinct immune signalling pathways”. These adjuvants have been the “primary focus” in vaccine design, but other noon-TLR-based adjuvants also present interest, including saponins like Quil-A. When delivered in nanoparticles (NPs), such as ISCOMATRIX, they are “well tolerated”.
Although the mechanism of immune stimulation of self-assembled saponin-based nanostructure adjuvants has “not yet been fully elucidated”, research indicates that they increase lymph flow and lymph node (LN) permeability, enhancing antigen acquisition by B cells in the draining LNs (dLNs). Furthermore, there is a clear advantage in NPs formulation for “stability, solubility, cellular uptake, immunogenicity, and safety”.
What does this research add?
The paper reports a “library” of saponin-based NP adjuvants incorporating various single or multiple clinically relevant TLRas (TLRa-SNPs) to generate a “broadly applicable” modular platform. Four formulations were generated, and all four elicited “improved humoral immune responses”.
The adjuvant platform combines three approaches:
- Molecular TLRa adjuvants resembling pathogen-associated molecular patterns found on bacteria, viruses, and other foreign invaders our immune system is trained to recognise
- Saponin adjuvants from natural sources that improve lymphatic flow
- Particulate design displaying both adjuvants together with improved trafficking kinetics and cellular uptake
Although previous studies have reported the design of combined TLR4a MPLA and saponins into NP constructs, the authors highlight that a “tunable” platform approach should consider other clinically relevant TLRas. Therefore, they demonstrated that lipid TLRas like MPLA and Pam3CSK4 can be “readily incorporated with clinically relevant stoichiometric ratios due to the hydrophobic nature of SNPs”. Nonlipid TLRas can be incorporated by conjugating a cholesterol motif with hydrophobic interactions with SNPs.
Dr Eric Appel, associate professor of material science and engineering at Stanford, is senior author of the paper. He comments on the “stronger, more robust immune responses” and states that the “breadth” of the platform “allows us to readily tune the type of immune response in a way that just was not feasible with previous technologies”.
“This can be a tool to understand how different types of immune responses give rise to better or worse protection – it was impossible to even ask that question before.”
Dr Appel highlights two key benefits from the research.
“This platform approach will open up opportunities for people in the field to ask more probing questions about what immunology works better in different contexts. And it’s also making significantly better adjuvants.”
PhD student in Appel’s lab and first author of the paper, Ben Ou, wanted to create a highly potent adjuvant to “activate different immune pathways and improve vaccine responses”.
“All of our adjuvants improve overall vaccine responses, but the specific types of improvements are different. If we know that a specific type of immune activation will confer better protection, we now have a platform that will allow you to pick the specific formulation that will drive that distinct response.”
Several sessions at the Congress in Barcelona will enable discussions on adjuvant potential and how to achieve it; get your tickets to join us here and don’t forget to subscribe to our weekly newsletters for more vaccine updates.
by Charlotte Kilpatrick | Aug 7, 2024 | Technology |
In August 2024 Phylex Biosciences announced the publication of a preprint presenting research into the immunogenicity of its Nipah mRNA nanoparticle vaccine candidate. The paper, co-authored with CDC scientists, found that the vaccine elicited a “robust” neutralising antibody response in mice. Neutralising titers were “markedly higher” than other Nipah vaccine designs and demonstrated “efficient neutralising even with a single dose”.
Nipah virus
Nipah virus (NiV) is a zoonotic virus that causes human infections ranging from asymptomatic to acute respiratory infection or fatal encephalitis. There are no drugs or vaccines approved for Nipah virus infection, and WHO considers Nipah virus a priority disease for focused research and development efforts.
Phylex’s technology
Phylex states that “recent progress in computational analysis and artificial intelligence deep learning” enable the design of antigens that elicit specific classes of neutralising antibodies. The Nipah vaccine antigen is based on the head domain of the G attachment protein of the virus, displaying “most epitopes of neutralising antibodies”. In virus neutralisation assays, the vaccine-elicited sera had neutralisation titers that were “3-fold the average titers” of 14 individuals who survived Nipah virus infection in Bangladesh. The antigen is displayed on a self-assembling nanoparticle “directly encoded” by mRNA.
“The pursued advantages of our nanoparticle vaccines are longer protection, protection against viral dissemination and associated neuropathology, and reduction of the number of challenges necessary for immunisation.”
Pascal Brandys, co-founder and CEO of Phylex Biosciences, is “grateful” to the CDC co-authors for their contribution to the vaccine assessment.
“The results confirm the strong advantage of our mRNA vaccine encoding for a highly immunogenic nanoparticle, as compared with a variety of other technologies.”
Brandys states that the vaccine “combines the advantages of mRNA for speed of manufacturing and development and a nanoparticle for efficacy after one dose”.
“We will aggressively pursue the clinical development of our vaccine candidate to initiate clinical trials with exposed individuals on a compassionate bases and save lives as soon as possible.”
To learn more about innovative vaccine development strategies at the Congress in Barcelona this October, why not get your tickets to join us here? Don’t forget to subscribe to our weekly newsletters for regular updates!
by Charlotte Kilpatrick | Aug 5, 2024 | Technology |
In August 2024 the Access to Advanced Health Institute (AAHI) announced an expanded partnership with Afrigen Biologics to develop effective vaccines using AAHI’s innovative adjuvant formulations in sub-Saharan Africa. This develops a longstanding joint commitment that was initially focused on advancing a tuberculosis vaccine candidate that combines AAHI’s recombinant ID93 protein and GLA-SE adjuvant formulation. The expansion seeks to advance life-saving vaccines in Africa to provide “affordable and easily accessible protection from disease”. The collaboration will address multiple infectious diseases of special concern in sub-Saharan Africa, using AAHI’s adjuvant and formulations expertise to develop cost-effective vaccines that provide broad and long-lasting protection and can be easily manufactured, distributed, and administered.
Aligned efforts
AAHI states that Afrigen’s “continued efforts to build vaccine development capacity in Africa” are “directly aligned with AAHI’s efforts to provide vaccine platforms that enable globally distributed manufacturing for local self-reliance”. This enables “sustainable protection against disease”.
Professor Petro Terblanche, Afrigen’s Chief Executive Officer, highlights that the partnership “further enhances Afrigen’s adjuvant formulation capacity and capabilities”. Professor Terblanche reflects that Afrigen created the first adjuvant formulation laboratory on the continent in 2018 with a technology transfer from AAHI. Through local and international collaborations, Afrigen developed a “library” of next generation formulated adjuvants for vaccine development focusing on HIV, TB, and zoonotic diseases that are “aligned with One Health priorities”.
“This expanded partnership will allow Afrigen to support the development adjuvanted vaccines relevant to the burden of disease in African and to contribute to pandemic response and preparedness.”
Dr Corey Casper, President and Chief Executive Officer at AAHI, comments that “more than half of all deaths in sub-Saharan Africa are attributed to infections”.
“Vaccines provide one of the most effective and cost-efficient means of reducing this disease burden, which encompasses both communicable disease and non-communicable diseases like cancer and heart disease.”
Dr Casper is “committed” to making AAHI’s vaccine technologies “easily accessible and affordable to people around the globe”. An “important way” of doing this is partnering with local vaccine manufacturers.
“Afrigen is a longstanding and trusted partner that is especially well-poised to make this vision a reality.”
VaccineNation was lucky to speak to Afrigen’s Professor Terblanche at the Congress in Washington in 2023 and AAHI’s Candice Decaire in Washington in 2024 to hear more about the work that their organisations are doing in the vaccine space. We look forward to welcoming Professor Terblanche back to the European Congress this October, so do get your tickets to hear more there. We will also welcome Professor Terblanche and senior representatives from AAHI to the Washington Congress in April; get your tickets to join us there and don’t forget to subscribe for more vaccine updates.
by Charlotte Kilpatrick | Aug 1, 2024 | Technology |
In August 2024 Valneva and LimmaTech announced that they have entered a strategic partnership and exclusive licensing agreement for the development, manufacture, and commercialisation of Shigella4V (S4V), a tetravalent bioconjugate vaccine candidate against shigellosis. LimmaTech will receive an upfront payment of €10 million and will be eligible to receive further regulatory, development, and sales-based milestone payments as well as royalties on sales. LimmaTech will lead on a Phase II Controlled Human Infection Model (CHIM) and a Phase II paediatric study in low- and middle-income countries (LMICs). These trials are expected to begin in the second half of 2024. Valneva will cover other areas of development, including CMC (chemistry, manufacturing, and controls) and regulatory activities, as well as worldwide commercialisation if approved.
Shigellosis
Shigellosis is caused by the Gram-negative Shigella bacteria. In 2016 it was the second-leading cause of diarrhoeal mortality across all ages. The US CDC suggests that it causes an estimated 80 million – 165 million cases of disease and 600,000 deaths annually; most of these are among children. The development of Shigella vaccines is a WHO priority, but there is currently no approved vaccine. Valneva estimates that the global market for a vaccine against Shigella exceeds $500 million annually. Standard treatment for shigellosis is oral rehydration and antibiotic therapy, but the bacteria have developed resistance to many antibiotics and there are reports of outbreaks of multidrug-resistant strains.
Shigella4V
LimmaTech signed a research collaboration agreement with GSK in 2015 to develop novel, bioconjugate antigen-based vaccines. Among them was a monovalent Shigella vaccine; after positive results in a proof-of-concept trial, LimmaTech and GSK initiated the development of a multivalent vaccine. In 2023 LimmaTech announced that it had in-licensed the candidate from GSK to lead further development. The candidate is a tetravalent bioconjugate vaccine targeting four predominant pathogenic Shigella serotypes. In February 2024 LimmaTech reported positive interim Phase I/II data for the S4V vaccine candidate, including a favourable safety and tolerability profile.
A promising programme
Thomas Lingelbach, Valneva’s CEO, is “very pleased” to partner with LimmaTech to advance the “promising programme in an area of high-unmet medical need”. He believes that the vaccine candidate enables a “potential first-in-class vaccine solution” for LMICs and travellers, representing a “potentially highly synergistic product”.
“The anticipated development path follows a staggered and risk-mitigated strategy, and hence allows and efficient capital allocation in line with our communicated plan of having a new R&D programme in Phase III by 2027.”
CEO of LimmaTech, Dr Franz-Werner Haas, is “excited to accelerate the programme” through the partnership with Valneva. The LimmaTech has taken the vaccine candidate from early discovery to “promising clinical data” and now welcomes Valneva’s “proven expertise” in late-stage development and commercialisation.
“This agreement underscores our capabilities to leverage LimmaTech’s proficiency in vaccine development with the best path to develop programmes rapidly. We continue to expand our pipeline of vaccine candidates to combat microbial-based infectious diseases, providing protection against antimicrobial resistance, a dramatically increasing global health threat.”
We look forward to welcoming senior representatives from both LimmaTech and Valneva to the Congress in Barcelona this October, so get your tickets to join us there and don’t forget to subscribe to our weekly newsletters here.
by Charlotte Kilpatrick | Jul 31, 2024 | Technology |
Biological E announced in July 2024 that WHO has granted prequalification status to the company’s Novel Oral Polio Vaccine type 2 (nOPV2). Biological E describes this as a “monumental stride” towards global polio eradication, celebrating the 10th Biological E vaccine to receive this status. nOPV2 is a next-generation live, attenuated oral vaccine that “significantly reduces” the risk of circulating vaccine-derived poliovirus type 2 (cVDPV2) outbreaks and is intended for use in countries affected by these outbreaks in a “crucial moment in the fight against polio”.
A strong candidate
Biological E states that nOPV2 can tackle the “persistent threat” of circulating cVDPV2; the vaccine boasts “improved genetic stability” with a “significantly” lower risk of “seeding new outbreaks” in low-immunity environments, compared to the Sabin poliovirus type 2 (mOPV2) vaccine. Through “extensive” clinical trials the safety and immunogenicity of nOPV2 have been “rigorously” evaluated. Furthermore, use in outbreak regions has shown that nOPV2 can “significantly” decrease the incidence of cVDPV2 outbreaks.
Mahima Datla, Managing Director of Biological E, is “pleased to be a part of the global effort to eradicate polio”.
“Our collective quest to eradicate polio marks a significant milestone with the WHO prequalification of nOPV2. This vaccine has been specifically designed to address concerns about vaccine-associated paralytic polio (VAPP), which has occurred in approximately 2 to 4 cases per million births with the traditional OPV due to the vaccine virus reverting to a virulent form.”
Ms Datla also recognised the role of key collaborator PT Bio Farma (PTB) in Indonesia and supporter, the Bill and Melinda Gates Foundation. The Gates Foundation provided a grant to support efforts to meet the global demand. She described the PTB collaboration as a “privilege” and extended “heartfelt gratitude” to the Gates Foundation for “entrusting us with the responsibility of manufacturing nOPV2”.
“Together we are committed to advancing the cause of global health equity and guaranteeing that no child is affected by the devastating effects of polio. The significance of this milestone extends beyond scientific achievement; it represents a beacon a hope for millions of children and families around the globe.”
Ms Datla states that administering more than 1 billion doses of nOPV2 in outbreak regions is “crucial to realising the dream of a polio-free world”.
We look forward to welcoming Dr Ajoy Chakrabarti, Portfolio and Platform Lead, Polio, Global Health Programme, Gates Foundation to the Congress in Barcelona this October; get your tickets to join us here and don’t forget to subscribe to our weekly newsletters here.
by Charlotte Kilpatrick | Jul 31, 2024 | Technology |
ApiJect announced in July 2024 that a peer reviewed study comparing the environmental footprint of the company’s prefilled injection device to traditional glass syringe options found a “substantial difference” in favour of the Prefilled Injector. The study identified and measured every step in the production and distribution processes of different injection devices to quantify environmental footprint and CO 2 release. In all categories of resource use and environmental impact, ApiJect’s device outperformed the other devices.
Highlights from the study
The study finds that ApiJect’s Prefilled Injector results in 38g of CO 2 –eq per dose. This compares with:
- Single-Dose Glass Vial: ~125% higher per dose
- Luer-type Prefilled Syringes: ~100% higher per dose
- Multi-Dose Vial and Staked-type Prefilled Syringes: 65%-75% higher per dose.
In measuring water use for manufacturing, cleaning, and sterilisation, the study suggests that a typical single-dose glass vial requires over 100 times more water than the Prefilled ApiJect Injector. Across the 10 impact categories in the TRACI (Tool for Reduction and Assessment of Chemicals and other environmental Impacts) 2.2 method, the Prefilled ApiJect Injector has the “lowest environmental impact”.
Dr Matthew Eckelman, report co-author, believes that the findings “should be of great interest to anyone who cares about the environmental impact of medicines”. He reflects that “health care and its supply chains are important contributors to greenhouse gas (GHG) emissions.
“The report shows that the carbon footprints of traditional glass-based injectable medicines fill-finish options are approximately 65% to 125% higher than ApiJect’s innovative platform, and they require more energy, materials, and water.”
Co-author Dr Robert Litan also comments that the reduction of greenhouse gases “is a business imperative” for today.
“This report shows that yesterday’s technologies and manufacturing processes won’t get it done. By measuring the environmental impact of each step in product manufacturing and distribution, we are able to quantify to a high degree of specificity the levels of greenhouse gases reductions achieved by a new innovative injection device compared to traditional injection products.”
Sustainable immunity
CEO of HIPRA Human Health, Carlos Montañés, shares that “reducing the carbon footprint and the environmental impact of our products are priorities for HIPRA”. The ApiJect project “attracted our attention” for its innovation and potential to improve logistics and global access to vaccines.
“This study’s findings show that in addition to the benefits to the supply chain, ApiJect’s devices also provide a significant advantage by reducing the environmental footprint. Therefore, with the combination of our vaccines, such as our recombinant protein vaccine against COVID-19, and ApiJect technology, we could be providing immunity for a healthier world in a more sustainable way.”
ApiJect’s co-founder and the inventor of the Auto-Disabled Syringe, Marc Koska, shares that “for some time we have intuitively believed that the ApiJect device was far more environmentally friendly” than traditional options. However, this study offers “data-driven results” that show “far greater advantages than we ever assumed”.
“Their findings are not marginal differences. Just as the Auto-Disabled Syringe has prevented syringe reuse and saved countless lives around the world, the ApiJect device’s lower emissions will contribute to a more environmentally healthy planet.”
Jay Walker, ApiJect co-founder, highlights that the ApiJect injection platform was built to “deliver an affordable prefilled option for most, if not all, injectional medicines”. It is supported by a “high-volume manufacturing process and compact supply chain”.
“The Eckelman-Litan study shows that our most important contribution to global health may be our impact on the environment. As we file for regulatory approval for our initial device in the coming months, expand our manufacturing capacity here in the US, and partner with a growing list of pharmaceutical companies to launch regulatory reviews of their drugs in our device, we will begin to see environmental impacts.”
To learn more from ApiJect about the potential offered by their innovative approach, why not join us at the Congress in Barcelona this October? Don’t forget to subscribe to our weekly newsletters here.
by Charlotte Kilpatrick | Jul 30, 2024 | Technology |
GSK and Flagship Pioneering announced in July 2024 that they have entered a collaboration to discover and develop a portfolio of “transformational” medicines and vaccines, starting in respiratory and immunology. The agreement will combine GSK’s “disease area expertise and development capability” with Flagship’s “ecosystem of bioplatform companies”, including novel modalities and technologies. The two organisations seek to achieve “major advances” in healthcare.
Building up to a portfolio
GSK and Flagship will begin with $150 million funding to support an “exploration phase” to identify the “most promising concepts” for research and development with Flagship’s bioplatform companies. Following this, the collaboration is intended to identify a portfolio of up to 10 novel medicines and vaccines. These will be subject to an exclusive option by GSK for further clinical development. Flagship and its bioplatform companies will be eligible to receive up to $720 million in upfront, development, and commercial milestones from GSK, alongside preclinical funding and tiered royalties, for each programme acquired.
Chief Scientific Officer at GSK, Dr Tony Wood, looks forward to partnering with the “talented team at flagship” and their bioplatform “ecosystem” to accelerate the pipeline and identify “practice-changing medicines and vaccines”.
“We will use science and technology to deliver best-in-class innovation at pace.”
Flagship’s General Partner and President, Pioneering Medicines, Paul Biondi, identifies a “shared focus on delivering breakthrough medicines for patients”.
“This collaboration is the latest example of Flagship’s Innovation Supply Chain Partnership model, which is designed to generate transformational medicines together with our pharma partners by leveraging our ecosystem of first-in-category bioplatforms to create a sustainable source of treatments for patients with the greatest unmet needs.”
If you’re interested in hearing more on vaccine partnerships, why not come to the Partnerships and Access Track at the Congress in Barcelona this October to learn more from field leaders? Don’t forget to subscribe to our weekly newsletters here for the latest vaccine news.
by Charlotte Kilpatrick | Jul 29, 2024 | Technology |
In July 2024, WHO announced that Argentine manufacturer Sinergium Biotech is to lead a new project that aims to accelerate the development and accessibility of human avian influenza (H5N1) mRNA vaccine candidates for manufacturers in low- and middle-income countries (LMICs). The project will leverage the WHO and Medicines Patent Pool (MPP) mRNA Technology Transfer Programme, which was launched in July 2021 to build capacity in LMICs for the development and production of mRNA-based vaccines. Sinergium is a partner in the Programme and has developed candidate H5N1 vaccines. If it establishes preclinical proof-of-concept the technology, materials, and expertise will be shared with partners, “aiding the acceleration” of the development of these candidates and “bolstering pandemic preparedness efforts”.
The mRNA Technology Transfer Programme
Since its inception, the mRNA Technology Transfer Programme has already developed and implemented a platform that has been used to establish the immunogencity, efficacy, and safety of a COVID-19 vaccine candidate in preclinical models. The platform was created and validated at Afrigen and is now being shared with partners for applications against “other critical disease targets”.
WHO Director General Dr Tedros Adhanom Ghebreyesus, states that the initiative “exemplifies” why WHO established the Programme to “foster great research, development, and production”.
“When the next pandemic arrives, the world will be better prepared to mount a more effective and more equitable response.”
Charles Gore, MPP’s Executive Director, reflected that the goal of the Programme is to “enable low- and middle-income countries to lead development efforts, foster collaboration, share resources, and disseminate knowledge”.
“This project embodies our vision and demonstrates a strong commitment to future pandemic preparedness and response.”
Rising to the avian influenza challenge
WHO states that avian influenza viruses are a “significant public health risk” due to “widespread circulation in animals” and “potential to cause a future pandemic”. Thus, the latest project complements work to improve and strengthen the sharing of influenza viruses with human pandemic potential and increase LMIC access to vaccines. Dr Jarbas Barbosa, Director of the Pan American Health Organisation (PAHO), is pleased with the news.
“This announcement underscores the importance of not only geographically diversifying the innovation and production of health technologies including and recognising the capacities in Latin America and the Caribbean, but also the importance of early planning for access and the sharing of knowledge and technologies during the research and development processes.”
Chief Executive Officer at Sinergium is “excited to tackle this public health challenge” in collaboration with partners.
“Sinergium’s enhanced capacity and readiness to apply our expertise to H5N1 will play a vital role in this effort towards global pandemic preparedness. I would also like to thank PAHO who have also been instrumental through the strong support it offers to regional manufacturers in the Americas.”
The importance of technology transfers in building regional capacity and facilitating equitable vaccine distribution will be discussed in a panel at the Congress in Barcelona this October; get your tickets to join us here and don’t forget to subscribe to our weekly newsletters here.
by Charlotte Kilpatrick | Jul 18, 2024 | Technology |
An article in Infection in July 2024 summarises discussions held at a VACCELERATE Consortium workshop, which explored the applicability of adaptive platform trial (APT) methodology in vaccine trials for both non-pandemic and pandemic conditions. The authors suggest that an “ever-warm” APT could be “ideally suited to improve efficiency and speed” in vaccine research. The paper is particularly pertinent as APT methodology has not yet been “widely adopted” in vaccine clinical research.
VACCELERATE and the workshop
In 2021 the VACCELERATE Consortium was established as an “integral” element of the EU’s response to the COVID-19 pandemic. Led by University Hospital Cologne, the network provides a “research infrastructure for vaccine trials” and includes 31 national partners in 18 EU Member States and 5 countries associated with the EU Horizon 2020 research programme.
Earlier this year, University Hospital Cologne organised the VACCELERATE APT Workshop as a way of “aligning” APT stakeholders. It hosted attendees from a “wide range of disciplines and backgrounds” with the aim of understanding the potential that APT has for pandemic preparedness. The resulting paper reflects “core aspects” discussions that took place, including a call for a “paradigm shift” from the “traditional” two-arm randomised clinical trial (RCT) to a “continuously learning adaptive platform trial”.
APT
Platform trials can be considered “disease focussed” and offer flexibility and the potential to “speed up” the evaluation of products through the shared use of infrastructure. Furthermore, the standardised framework of a platform trail facilitates comparisons between arms and increases statistical efficiency through shared common control data.
“In the context of vaccine development, in both an interpandemic and pandemic context, platform technology needs to be tailored to the specifics of an infectious disease affecting potentially large populations, against the background of rapid evolution of both the mutating virus and the development of natural and vaccine-induced immunity.”
The authors state that an APT framework that is tailored to the specific context of infectious disease vaccine development is “ideally suited to improve efficiency and speed” of evaluation. An APT offers the “continual ability to learn and benefit” as data emerge, but “thorough” planning is required on adaptions based on beneficial data.
“An APT builds on the well-known features of “traditional” RCTs, in particular experimentation, randomisation, and blinding. In addition, an APT offers the flexibility of adaptation rules and the integration of information from other relevant data sources, such as sentinel surveys and other epidemiological studies.”
Various data can be integrated for “valuable enhancement” and mathematical modelling and health economics expertise will support the design, dynamic adaptation, and assessment of vaccination benefits.
Vaccine APTs should collect a “variety” of clinical endpoints and combine endpoints to “gauge efficacy”. Indeed, the choice of primary endpoint might “shift over time’. Alongside endpoints, markers should be collected for potential validation as correlates of protection, and both “classical – marginal – vaccine efficacy” and “conditional” vaccine efficacy will be relevant. Each development must take place in “continual dialogue” with regulators.
Transparency and co-creation between researchers and health authorities are emphasised. Furthermore, the authors suggest that the “complexity and flexibility” of a vaccine APT will demand “additional dedicated governing bodies”.
Pandemic and interpandemic context
“There is consensus that a vaccine APT set up in the context of pandemic preparedness should run perpetually, i.e, “ever-warm” or “warm-base” in the interpandemic interval, and have the built-in ability to pivot to pandemic mode at shortest notice.”
When not in a pandemic situation, a vaccine APT should be “constantly fed” relevant research questions to create an “uninterrupted flow of new evidence”. These will likely come from research gaps in industry trials and result in informed public health decision-making. Interpandemic vaccine APT trial activity should focus on pathogens causing acute respiratory infection (ARI), such as RSV, SARS-CoV-2, or avian influenza.
Investigations will “preferentially focus” on the most vulnerable populations, which are underrepresented in industry trials, but this does not preclude the enrolment of healthy all-comers in later trials on candidate vaccines. Approved vaccines should be investigated in vulnerable populations and research should target label extension/modification or “impactful practice change”.
“APT investigations in the interpandemic interval need to utilise a wide spectrum of clinical research activities to keep up quality at the trial sites, in terms of enrolment capacity, standards of documentation, workup of biosamples, and any related logistics.”
Key points from the workshop
The paper highlights a consensus that APT methodology can be applied to vaccine trials, supported by the existing blueprint of a large-scale vaccine APT prepared for a Marburg virus outbreak. Although APT designs are “more complex” they have the potential to “accelerate knowledge generation”. Workshop attendees agreed that, while designs may be complex, execution “must be simple and straightforward”. The authors note that workshop attendees assigned importance to the value of “soft factors” in maintaining a clinical research network, including trust and leadership.
Professor Oliver A. Cornely of the University of Cologne is coordinator of VACCELERATE and reflected that “COVID-19 made us realise how important it is to be able to react quickly to an emergency” and “adapt vaccine studies” as the situation changes.
“This can significantly speed up the time it takes to generate the data required for political decision-making. However, this requires a paradigm shift in the field of clinical vaccine research.”
Pandemic preparedness remains at the centre of many sessions on the agenda at the Congress in Barcelona this October, so do get your tickets to join these important discussions as we explore different elements of the challenge. Don’t forget to subscribe to our weekly newsletters here.
by Charlotte Kilpatrick | Jul 16, 2024 | Technology |
Researchers at the Hackensack Meridian Centre for Discovery and Innovation (CDI) shared in July 2024 that their paper in Cell Reports presents the identification of an “unconventional” immune response with positive implications for tuberculosis (TB) vaccine development. The authors suggest that, while understanding the role of B cells is “crucial” for TB vaccine development, the changes in B cell immune landscapes during TB remain “incompletely explored”. They used high-dimensional flow cytometry to “map” the immune landscape in response to Mycobacterium tuberculosis (Mtb) infection, concluding that targeting the regulatory function of B cells could be a valuable strategy for TB vaccine development.
TB vaccine challenges
Tuberculosis, caused by infection with Mycobacterium tuberculosis (Mtb), remains a “severe public health threat worldwide”, resulting in 1.6 million deaths a year. A key challenge in controlling the disease is the “lack of reliable vaccines”; the BCG vaccine has “varying efficacy” but the development of an alternative is “hampered by an incomplete understanding of the immune correlates for protection”.
Recent research has “predominantly” addressed T cells in Mtb infection, leaving B cells “not fully understood”. Thus, the authors hope to elucidate their role in immunity and protection and provide “valuable insights” for TB vaccine development. The role of B cells in Mtb infection is unclear, with studies suggesting it ranges from protective to neutral to detrimental.
B cells
B cells can provide a “broad defence spectrum against infections” with heterogeneous subsets displaying “distinct functional characteristics”. These subsets are divided into “conventional and unconventional” B cells based on functional characteristics and immunophenotypes:
- Conventional B cells, also known as follicular B (FoB) cells, represent the “major” B cell subset of around 80% of B cells. They are a “critical component” for adaptive immunity, reacting to infections with “high-affinity antibodies”.
- Unconventional B cells, including marginal one B (MZB) cells, B1 B cells, MZB cell precursors (MZPs), and age-associated B cells (ABCs), are components of innate immunity, responding to infections faster than FoB cells with “low-affinity antibodies”.
B cells “dynamically” change their subset compositions in response to TB, with MZB cell frequency increasing in the blood of active TB patients and the frequency of atypical B cells with ABC phenotype increasing in the blood of both active and latent TB patients.
“Notably, the successful treatment of TB has been found to reverse the alterations in B cell subset compositions. These observations suggest that B cells change their immune landscape in response to the varying status of Mtb infection.”
The study
To “comprehensively” investigate the detailed immune landscape of B cells, the authors used high-dimensional flow cytometry to analyse B cell subsets in infected organs of mouse models. They then depleted the specific B cell subset in mouse models to examine their functional implications on Mtb infection, finding that, in response to infection in the lungs and spleen, B cells “shifted” their immune landscape to favour MZB cells. This contributes to systemic protection by shaping cytokine patterns and cell-mediated immunity.
An important feature of the research is that MZB cells “continuously expanded” throughout Mtb infection, which implies their engagement in both early and chronic phases of TB. MZB cells presented an “activated and memory-like phenotype”, emphasising their “functional distinction” from conventional B cells. The expansion of MZB cells increased the pool of multiple-cytokine-producing B cells to shape systemic cytokine patterns. This means that the accumulation of MZB cells “not only changed the composition B cells throughout the infection but altered the effector functions of B cells”.
Pulmonary and splenic MZB cells exhibited “similar” immunophenotypes and RNA signatures but differed from conventional B cells. Pulmonary MZB cells “might perform functions analogous” to splenic MZB cells. MZB cells are “typically” found in the spleen of healthy mice but have been observed outside the spleen during disease progression or ageing, and the results confirmed the presence of B cells exhibiting the MZB phenotype and RNA signature outside the spleen during infection. However, the origins of the pulmonary MZB cells “remain uncertain”.
As a low frequency of MZB cells was detected in the blood of infected mice, the authors suggest that pulmonary MZB cells were unlikely to have disseminated from the spleen through the bloodstream. Instead, they consider that pulmonary MZB cells could be derived from local FoB cells, with B cell follicles in the infected lungs providing a “suitable environment” for the differentiation. FoB cells have been shown to differentiate into MZPs and then MZB cells with “appropriate stimulation”. Therefore, in response to Mtb infection, pulmonary FoB cells could acquire the MZB phenotype at both protein and RNA levels to “adopt the functions” of splenic MZB cells.
MZB cells during infection
During Mtb infection, MZB cells “displayed a distinct functional profile” in comparison with conventional B cells, exhibiting an “activated and memory-like phenotype”. They expressed higher levels of CD86 and CD80 than conventional B cells, possibly “empowering” them to regulate T and NK cells through interactions with CD28 family receptors. This is a “crucial” mechanism for TB control.
Although MZB cells are usually categorised as innate-like cells, the study suggests that memory-like B cells mainly accumulated in the MZB subset during infection. Additionally, with the “abundant” expression of CD69 on pulmonary MZB cells, they may have served as lung-resident memory B cells, contributing to long-term protection against Mtb infection.
The MZB cells protected against TB through a cytokine pattern that created an anti-TB environment. This is an “unorthodox regulatory function” that differs from conventional B cells. Indeed, the depletion of splenic MZB cells led to an increased Mtb burden and a cytokine pattern that “promoted” TB progression. Polyfunctional CD4 T cells play an “essential role” in controlling TB, and MZB cells reflected these characteristics to produce both TNF- α and IL-2 as well as CXCl1, CCL5, and GM-CSF.
“At the early stage of infection, MZB cells could provide multiple cytokines to serve as an innate defence mechanism, even before the onset of adaptive immunity, like polyfunctional T cells. With the progression of the infection, multiple-cytokine-producing MZB cells continued to expand, maintaining an anti-TB environment throughout the infection.”
Furthermore, MZB cells regulated the dynamics of other cytokine-producing cells through their capacities for multiple cytokine production and co-stimulatory ligand expression. They play a “key role” in executing the regulatory function to provide protection against TB.
“Our results indicate that B cells skew their immune landscape toward MZB cells to execute regulatory functions against TB, emphasising the importance of antibody-independent mechanisms of B cells for controlling infectious diseases, a previously neglected mechanism.”
The researchers hope that the insight they provide will “offer a promising avenue” for TB vaccine development.
“Enhancing MZB cell responses during BCG vaccination may improve vaccine efficacy by using their regulatory functions to shape optimal immune responses. Furthermore, activated and memory-like MZB cells may serve as tissue-resident memory B cells to provide long-term protection.”
For more on the latest research to optimise vaccine development, why not join us at the Congress in Barcelona this October, or subscribe to our weekly newsletters here?
by Charlotte Kilpatrick | Jul 15, 2024 | Technology |
Sabin Vaccine Institute announced in July 2024 that it has launched a Phase II clinical trial for its vaccine against Sudan ebolavirus. The trial of healthy volunteers takes place at Makerere University Walter Reed Project (MUWRP) in Uganda. The vaccine is based on the cAd3 platform and appeared “promising” in Phase I clinical and non-clinical studies. Ebolavirus disease kills “on average half the people infected”, and there are no approved vaccines for the Sudan strain.
Sudan ebolavirus
Sudan ebolavirus is a “lesser known” filovirus than Ebola Zaire. It can cause severe haemorrhagic fever in humans and nonhuman primates. It is transmitted to humans by infected animals, particularly fruit bats, and can then spread to others through close personal contact or contact with bodily fluids. The most recent outbreak of Sudan ebolavirus occurred in 2022 in Uganda, identified after six suspicious deaths in the Mubende district. The outbreak caused 55 deaths but concluded before a vaccine was deployed for use in an outbreak trial.
The vaccine in trial
In 2019 Sabin announced exclusive agreements with GSK to advance the development of prophylactic candidate vaccines against Zaire ebolavirus, Sudan ebolavirus, and Marburg virus. The Sudan ebolavirus candidate, based on the CAd3 platform, is a single-dose investigational vaccine that has proven safe and capable of eliciting “rapid and robust” immune responses in study
The latest trial will enrol 125 volunteers at MUWRP and the Kenya Medical Research Institute in Siaya, Kenya. It will evaluate the safety and immunogenicity through a randomised, placebo-controlled, double-blind approach. Participants will be monitored for a year and will include younger (18-50) and older (51-70) age groups.
Dr Betty Mwesigwa, deputy executive director of MUWRP and principal investigator at the site, is “pleased” to partner with Sabin again.
“Uganda has the most experience with Sudan ebolavirus outbreaks so we understand the importance of testing and researching an effective Sudan ebolavirus vaccine that could be used in the event of an outbreak.”
Sabin’s Chief Executive Officer, Amy Finan, is “delighted to advance a vaccine candidate that can thwart a deadly and devastating disease”. This is particularly important in the context of a “fairly recent outbreak” and lack of approved treatments.
“Sabin’s vaccine candidate is backed by strong safety and immunogenicity data, and we hope this trial will yield further evidence to move the vaccine closer to licensure.”
We look forward to exploring the most effective route to vaccine approval for disease like Ebola at the Congress in Barcelona this October. Get your tickets to join us here and don’t forget to subscribe for more vaccine news.
by Charlotte Kilpatrick | Jul 12, 2024 | Technology |
Oxford’s Pandemic Sciences Institute announced in July 2024 that a clinical trial to test a vaccine against Marburg virus has been launched. The first-in-human trial of the ChAdOx1 Marburg vaccine, developed and manufactured by teams at the University of Oxford, will be led by the Oxford Vaccine Group. 46 people between the ages of 18 and 55 will participate. The research has been funded by the Department of Health and Social Care within the UK Vaccine Network, which seeks to develop vaccines for diseases with epidemic potential in low- and middle-income countries.
Marburg virus
WHO describes Marburg virus disease as a “highly virulent” disease that causes haemorrhagic fever; it has a fatality ratio of “up to 88%”. It belongs to the Filoviridae family, like Ebola, and is “clinically similar”. Human infection initially results from “prolonged” exposure to mines or caves inhabited by Rousettus bat colonies. It then spreads through human-to-human transmission via direct contact with the blood, secretions, organs, or other bodily fluids of infected people, and with surfaces or materials contaminated with these fluids.
ChAdOx1
ChAdOx1 is a virus vector vaccine based on a modified simian adenovirus. It was developed in 2012 by researchers at the University of Oxford. Professor Dame Sarah Gilbert describes it as a “true platform technology”, with Oxford researchers exploring applications such as tuberculosis, Dengue, and Zika virus. Advantages of the platform include ease of production and stability, as well as the effective induction of both B and T cell responses.
Professor Teresa Lambe OBE is the trial’s Lead Scientific Investigator and described the “real concern” that the “devastating disease has started to spread even further”. It has “potential to cause a pandemic and inflict suffering on many”, even though outbreaks have “historically been small”.
“With no approved treatments for Marburg, developing a vaccine is critical. This Oxford trial is a first step towards developing a safe and effective vaccine to protect people from future outbreaks.”
Professor Lambe is joining us at the Congress in Barcelona this October to discuss the development of flexible and sustainable vaccine technologies; get your tickets to learn more and don’t forget to subscribe to our weekly newsletters here.
by Charlotte Kilpatrick | Jul 11, 2024 | Technology |
Seattle-based biotech Orlance announced in July 2024 that it has been awarded a Phase I Small Business Innovation Research (SBIR) grant from the US NIH to develop and optimise RNA vaccine formulations with its needle-free MACH-1 platform. The technology is intended to enhance the safety, stability, and efficacy of RNA vaccines for infectious diseases and cancer immunotherapy applications. MACH-1 is described as a “potentially significant advancement” in RNA vaccine delivery.
Meet MACH-1
MACH-1 is a needle-free vaccine platform that provides a “rapidly deployable, ambient stable, dose sparing, and easy to use product”. Orlance hopes it will increase immunisation in underserved regions by overcoming logistics or personnel difficulties and needlestick hesitancy. With pressurised gas, MACH-1 accelerates microparticles of DNA vaccines, RNA vaccines, or a combination. Vaccine microparticles penetrate the outer layer of skin to reach the epidermal layer, achieving intracellular delivery and transfection in local antigen presenting cells within the epidermis. This results in “robust” induction of systemic and mucosal antibody and cytotoxic T cell responses.
Compared to traditional lipid nanoparticle (LNP) RNA formulations, the MACH-1 platform uses dry, stable RNA-coated gold microparticles. It is needle-free and painless and ensures better stability at ambient temperatures with “significant supply chain advantages”.
Gene Gun project
The SBIR-funded project, “Gene Gun-delivered RNA vaccines”, is to be led by Orlance Principal Investigators Dr Hannah Frizzell and Dr Kenneth Bagley. They will aim to optimise RNA formulations for MACH-1 gene gun delivery to “maximise loading, maintain functional integrity, and ensure stability and immunogenicity”. The researchers will compare the effectiveness of MACH-1 delivered RNA vaccines against traditional LNP/RNA vaccines.
The 2-year grant provides $300,000 a year to enable Orlance to conduct preclinical studies, expected to “pave the way” for subsequent phases of development. Orlance has already received $13 million in SBIR funding, advancing MACH-1 towards readiness for initial regulatory filings in 2024. The company plans to initiate Phase I clinical trials for its lead infectious disease asset in 2025.
Kristyn Aalto, co-founder and CEO of Orlance, stated that the “breakthrough” of mRNA vaccines in recent years has “established the enormous potential of genetic (RNA and DNA vaccines”. However, there is still “significant work to do to improve utility and overall global health impact”.
“We are very grateful for NIH’s continued support and are rapidly accomplishing MACH-1 platform goals that could truly enhance the clinical research and impact of genetic vaccines.”
With a “well-developed” candidate portfolio and offerings across both DNA and RNA, Aalto hopes to “leverage the attributes of both platforms to provide ideal solutions tuned to the immunogenicity, protection, and durability profiles sought for specific indications”.
To hear the latest on innovative vaccine delivery approaches, why not join us in Barcelona for the Congress this October, or subscribe to our weekly newsletters here?
