by Charlotte Kilpatrick | Oct 21, 2024 | Global Health |
In October 2024 WHO certified Egypt as malaria-free after a “nearly 100-year effort” by the government and people to end the disease. WHO described this as a “significant public health milestone” for the country’s more than 100 million inhabitants. Egypt is the third country to receive this certification in the WHO Eastern Mediterranean Region, following the United Arab Emirates and Morocco.
Across the globe, 44 countries and 1 territory have achieved this status by proving beyond reasonable doubt that the chain of indigenous malaria transmission by Anopheles mosquitoes has been interrupted nationwide for at least the previous three consecutive years. A country must also demonstrate its capacity to prevent the re-establishment of transmission.
Malaria becomes history
WHO states that malaria has been traced back as far as 4000 BCE in Egypt; there is genetic evidence of the disease in Tutankhamun and other ancient Egyptian mummies. More recently, efforts to reduce human-mosquito contact began in the 1920s with the prohibition of rice cultivation and agricultural crops near homes. With much of the population living along the banks of the Nile River and malaria prevalence “as high as 40%”, malaria was designated as a notifiable disease in 1930.
By 1942, malaria cases in Egypt exceeded 3 million due to population displacement caused by the Second World War, the disruption of medical supplies and services, and the invasion of Anopheles arabiensis, which is a “highly efficient mosquito vector”. Egypt responded to the outbreak by establishing 16 treatment divisions and recruiting more than 4000 health workers. The Aswan Dam, completed in 1969, brought an additional risk of malaria as standing water provides a mosquito breeding ground. Thus, Egypt worked with Sudan to launch a “rigorous” vector control and public health surveillance project.
By 2001, malaria was “firmly under control”, encouraging the Ministry of Health and Population to work on preventing the re-establishment of local malaria transmission. Egypt “rapidly” contained a small outbreak in the Aswan Governorate in 2014. The recent certification recognises continued efforts and initiatives including the free provision of malaria diagnosis and treatment to the population, regardless of legal status, and health professionals’ training to detect and screen for malaria. The country also has “strong” cross-border partnerships with neighbours like Sudan, which have been “instrumental”.
The beginning of a new phase
Dr Tedros Adhanom Ghebreyesus, WHO Director-General, congratulated Egypt on its achievement.
“Malaria is as old as Egyptian civilisation itself, but the disease that plagued pharaohs now belongs to its history and not its future. This certification of Egypt as malaria-free is truly historic, and a testament to the commitment of the people and government of Egypt to rid themselves of this ancient scourge.”
Dr Tedros hopes that this will be an “inspiration to other countries in the region”, showing “what’s possible with the right resources and the right tools”. Deputy Prime Minister of Egypt H.E. Dr Khaled Abdel Ghaffar commented that the certification is “not the end of the journey but the beginning of a new phase”.
“We must now work tirelessly and vigilantly to sustain our achievement through maintaining the highest standard for surveillance, diagnosis and treatment, integrated vector management, and sustaining our effective and rapid response to imported cases. Our continued multisectoral efforts will be critical to preserving Egypt’s malaria-free status.”
Dr Abdel Ghaffar reaffirmed that the country will “continue with determination and strong will”. WHO Regional Director for the Eastern Mediterranean Dr Hanan Balkhy emphasised that the success is “not just a victory for public health but a sign of hope for the entire world”, including other endemic countries in the region.
“This achievement is the result of sustained, robust surveillance investments in a strong, integrated health system, where community engagement and partnerships have enabled progress. Furthermore, collaboration and support to endemic countries, such as Sudan, remain a priority.”
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by Charlotte Kilpatrick | Oct 8, 2024 | Therapeutic |
A study in the Journal for ImmunoTherapy of Cancer finds that vaccination in a clinically relevant genetic cancer mouse model generated a population of functional progenitor tumour-specific CD8 T cells (TST) and halted cancer progression, in contrast to immune checkpoint blockade (IBT) therapies. The authors hope that immunisation could be the “most effective strategy” for patients with early cancers or at high risk of cancer recurrence. This study takes a different approach to many cancer vaccine studies, which tend to focus on patients with advanced tumours.
Cancer vaccine potential
The authors recognise the transformational role of immunotherapies in the cancer treatment landscape, particularly in the case of immune checkpoint blockade (ICB). However, vaccines for non-viral cancers have had “more limited success”. Many studies on tumour-specific CD8 T cell (TST) vaccine responses are conducted in the established/late tumour setting, so less is known about how TST “respond and differentiate” in response to immunotherapy during early stages of tumorigenesis.
Previously, the authors developed an autochthonous mouse model of liver cancer (AST;Cre-ERT2) to initiate liver carcinogenesis with tamoxifen (TAM)-induced Cre-mediated SV40 large T antigen (TAG) expression in hepatocytes. TAG functions as an oncogene and a tumour-specific neoantigen recognised by CD8 T cells, so the model enables “precise temporal control” of the duration of TST interactions with transformed hepatocytes and tumours. In contrast to human tumours, which “arise sporadically and progress clonally”, TAM-induced oncogene induction is “highly efficient”, resulting in high antigen burden even at early stages.
The study
The researchers allowed AST;Cre-ERT2 mice to undergo stochastic TAG oncogene activation through sporadic, TAM-independent Cre-mediated activity. To explore TST responses against TAG-driven tumours they used congenic donor lymphocytes from transgenic mice, in which CD8 T cells express a single T cell receptor (TCR) specific for TAG epitope-I (TCRTAG). They found that TST became dysfunctional in TAM-treated AST;Cre-ERT2 mice and were “unable to halt tumour progression”. TAM-treated AST;Cre-ERT2 mice had a “substantial” tumour antigen burden, even at early stages of tumorigenesis.
To compare initial TST differentiation in mice with early liver lesions against those with late liver lesions, the researchers transferred CFSE-labelled naïve TCRTAG into early and late time point AST;Cre-ERT2 mice. TCRTAG in mice with early lesions divided at a slower rate, particularly in the spleen and ldLN, and there were fewer TCRTAG in the spleens, ldLN, and livers of early mice. Decreased TST proliferation in mice with early lesions could be due to the lower TAG antigen burden. Although nearly all TCRTAG in mice with late lesions and most in mice with early lesions failed to produce effector cytokines TNFα and IFNγ within 60 hours of transfer, a population of TCRTAG in were identified in the spleen and liver of mice with early lesions. These could produce effector cytokines TNFα and IFNγ.
“Thus, in hosts with sporadic early lesions, a subset of TST resisted rapid differentiation to the dysfunctional state, raising the possibility that this subset might be amenable to immunotherapeutic reprogramming/rescue.”
To see if this functional TST subset persisted, the authors examined TCRTAG immunophenotype and function 5 days and 21 days post-transfer into early or late AST;Cre-ERT2 mice. While fewer TCRTAG were found in mice with early lesions compared to late lesions at 5 days, the difference became less pronounced at 21 days. In both groups TCRTAG upregulated CD44, which indicates antigen exposure and activation. TCRTAG in early mice continued to express higher levels of PD1 than naïve TCRTAG, suggesting that PD1 expression can identify tumour-reactive TST in hosts with early lesions.
The next consideration was if the functional TST subset in mice with early lesions could be harnessed to stop tumour progression. LM, a gram-positive intracellular bacterium, induces strong CD4 and CD8 T cell responses. The researchers used an actA inIB deficient attenuated LM vaccination strain to test if early vaccination of AST;Cre-ERT2 would protect mice against liver cancer progression. Mice were either left untreated, given a single dose of empty LM, or vaccinated with a single dose of LM- TAG.
“LM- TAG–immunisation conferred a major survival advantage, with all mice remaining tumour-free and one mouse euthanised for dermatitis without any evidence of liver tumours.”
The mice in untreated and empty LM groups reached endpoint with “multiple” large liver tumours and increased liver weight. At endpoint, most TCRTAG in the LM- TAG–immunised made effector cytokines, in contrast to the TCRTAG in tumour-bearing mice in the other groups, which were “largely unable to produce effector cytokines”.
Vaccination vs ICB
“An important and open question in cancer immunotherapy is how ICB versus vaccination compares in boosting anticancer immune responses, and how best to combine and sequence these therapies.”
A comparison of ICB, LMTAG vaccination, and combined ICB/LMTAG vaccination found that ICB conferred no benefit in comparison with isotype control antibodies (iso). By contrast, LMTAG and ICB/LMTAG treated mice had no evidence of tumour progression at 400+ days. Furthermore, LMTAG vaccination, whether alone or in combination, led to a “substantial increase” in TST numbers and IFNγ production, while ICB alone had “little impact”.
LM-based vaccines have had “poor or mixed results” in clinical trials, often with a target of patients with advanced or refractory cancers. The authors hope that their studies offer “mechanistic insight” as to why these fail in patients with advanced cancers: “for vaccines to be effective, a progenitor TST population must be present”. Although the apparent superiority of vaccination over ICB “may be surprising at first glance”, the authors highlight an important point, that “not all TCF1+TST are functional, nor does ICB alone lead to functional TST”. However, the findings suggest that LMTAG vaccination maintains or rescues functional progenitor TCF1+TST.
Timing is important
Dr Mary Philip, associate director of the Vanderbilt Institute for Infection, Immunology, and Inflammation, commented that the study “suggests that the timing of vaccination is important”.
“A unique feature of our study is that these mice are at high, essentially 100% risk of developing cancers, so the fact that a single immunisation at the right time can give lifelong protection is pretty striking.”
Dr Philip reflected that very few studies follow mice “so long after vaccination” and find them tumour free for two years.
“ICB works by taking the brakes off T cells, but if the T cells have never been properly activated, they are like cars without gas, and ICB doesn’t work. The vaccination boosts the T cells into a functional state so that they can eliminate early cancer cells.”
For more progress updates from cancer vaccine researchers at the Congress in Barcelona this month, get your tickets to join us here. Don’t forget to subscribe to our weekly newsletters here.
by Charlotte Kilpatrick | Oct 1, 2024 | Therapeutic |
In an article for npj vaccines in October 2024, researchers present their investigation into the efficacy of a combination of DNA vaccine encoding mouse GPRC5D and PD-1 in preventing and treating multiple myeloma (MM). MM “remains largely incurable”, but the GPRC5D, “highly expressed” in MM, presents a “compelling” immunotherapy candidate. The research suggests that GPRC5D-targeted DNA vaccines are “versatile platforms” for treating and preventing MM.
Managing MM
Multiple myeloma (MM) is the second most prevalent haematological malignancy, characterised by the accumulation of malignant plasma cells in bone marrow. Most MM cases are preceded by monoclonal gammopathy of undetermined significance (MGUS), which can reduce a person’s life expectancy by “more than 4 years”. Around 3.5 million people are affected by MGUS in the United States. Smouldering MM (SMM), distinguished from MGUS for clinical reasons, is an asymptomatic clonal plasma cell disorder between MGUS and MM.
MM treatment has been “transformed with the advent of antibody-based therapies”, with chimeric antigen receptor (CAR) T-cell therapies that target the B-cell maturation antigen (BCMA) showing “considerable promise”. However, the pattern of BCMA expression is heterogeneous, responsible for “varied treatment responses” and the surface expression can “fluctuate” because of gamma secretase-mediated shedding of the extracellular domain. Furthermore, antigen escape has been noted in patients with MM who experienced relapse after BCMA-targeted CAR T-cell therapy.
“Exploring immunotherapies targeting alternative antigens may help counteract antigen escape and provide effective treatment options for patients who relapse after BCMA-targeted CAR T-cell treatment.”
A new vaccine target
C protein-coupled receptors (GPCRs) are the “largest and most diverse” group fo membrane receptors in eukaryotes; humans have almost 1000 different GPCRs. GPCRs are classified into six classes (A-F), among which class C GPCRs initiate metabolic steps to modulate cellular activity.
Orphan GPCR class C group 5 member D (GPRC5D) is expressed in the hair follicle and the bone marrow of patients with MM, as well as in MGUS and SMM. The GPRC5D mRNA is overexpressed between two and four times in MM plasma cells compared to normal plasma cells, and immediate expression is seen in MGUS and SMM.
“GPRC5D is an emerging novel immunotherapeutic and preventive target for MM.”
Although DNA vaccines are a “promising” alternative to mRNA vaccines, with “lower cost and better stability”, they have not yet been widely adopted in clinical practice. DNA cancer vaccine development faces “significant challenges” such as nonspecific formulations, thermal instability, toxicity, and ineffectiveness. However, the authors believe that recent advancements have “greatly enhanced” the clinical efficacy of DNA vaccines in cancer treatment.
The study
In their research, the authors attempted to develop DNA vaccines against MM using plasmids expressing GPRC5D. First, they evaluated a mouse GPRC5D DNA vaccine in the 5TGM1 murine myeloma model, which “closely mimics” human MM. Cancer prevention activity was examined through administration of the DNA vaccine before tumour cell inoculation. The mice that received the mGPRC5D vaccine developed “significantly smaller” tumours than the control mice, and all animals in the mGPRC5D group were alive at day 33.
With ELISA, the authors evaluated the humoral response by measuring the levels of mGPRC5D-specific antibody in the serum collected 5 days after boost. They found a “marked increase” in serum IgG levels in the mGPRC5D group. To explore the possible mechanisms of the antitumour effect of the vaccine, they analysed immune cells in the spleen and tumours through flow cytometry. The percentage of various immune cell populations “significantly increased” in the mGPRC5D-immunised mice.
The research also considered the therapeutic efficacy of the mGPRC5D vaccine in combination with PD1 Ab treatment. After tumour inoculation, mice received two injections of 20µg mGPRC5D vaccine or the control plasmid at 2-week intervals, along with intraperitoneal administration of anti-PD1 antibody. Mice that received either the vaccine or anti-PD1 Ab showed a “moderate inhibitory effect”, but those treated with the combination exhibited “significant inhibition of tumour development”.
When comparing tumour weights in mice, the authors found “significantly” lower weights in the mGPRC5D and PD1 Ab group than in the control group or each monotherapy group. They also assessed the ability of the vaccine to induce TNFα or IFNγ responses in mouse splenocytes with the ELISPOT assay. Splenocytes from mice that received either mGPRC5D or PD1 Ab exhibited a “significant” increase in the number of spots, and a further increase was observed in the group that had the combination. The combination group had higher frequencies of TNFα+CD8+, IFNγ+CD8+, TNFα +CD4+, and IFNγ+CD4+ T cells in the spleen.
In a flow cytometric analysis of immune cell populations in the spleen, the authors found that treatment with mGPRC5D increased the frequency of CD4+ T cells by over 150% and CD8+ T cells by over 30%. PD1 Ab treatment increased the frequency of both cells by more than 100%. The combination had a “more pronounced effect”; CD4+ T cells increased more than 350% and CD8+ T cells increased by more than 130%. Similar observations were made for DCs, Mϕ, and NK cells in the spleen. For tumour-infiltrating lymphocytes (TILs), the combination approach increased the population of CD8+ and CD4+ T cells, DCs, Mϕ, and NK cells more than the monotherapies.
A human vaccine
As the peptide sequences of mGPRC5D and hGPRC5D are only ~81% identical, a human version of the vaccine is needed. The researchers developed a nanoplasmid construct expressing human GPRC5D (Nano-hGPRC5D). Prophylactic studies found that tumour growth was “significantly suppressed” in the mice group that received Nano-hGPRC5D, which also presented a “marked increase” in serum IgG levels. Other findings include a “significant increase” in the levels of cytokines in the Nano-hGPRC5D group, which suggests a “robust activation of inflammatory cytokines” upon vaccination.
In the spleen and tumours of hGPRC5D-immunised mice, percentages of CD3+, CD4+, and CD8+ T cells and DCs were “significantly increased”. Furthermore, higher frequencies of Th1 secretory cytokine-positive CD3+ T cells were observed in this group. A long-acting protective effect against tumours was implied in “significantly higher percentages” of effector and central memory T cells in the splenocytes of the hGPRC5D group. CD8+ T cells stimulated with the hGPRC5D peptide pool exhibited “superior proliferative ability” compared to the control.
Therapeutic combination
To evaluate the therapeutic efficacy of Nano-hGPRC5D in combination with PD1 Ab, the authors used syngeneic murine models. The combination resulted in “significant tumour regression” compared to either treatment alone. Levels of TNFα, IFNγ, IL-6, IL-12p40, and IL-12p70 increased “significantly” in the combination group, and ELISpot analysis revealed more TNFα- or IFNγ-positive cells in the combination group.
In a flow cytometric analysis of immune cell populations in the spleen and tumour, the combination caused an increase in effector CD8+ and CD4+ T cells, DCs, Mϕ, and NK cells, but a decrease in Treg cells. H&E staining of tumour sections revealed necrotic lesions in the hGPRC5D and combination groups, but the lack of gross histological damage in several major organs supports the safety and clinical potential of the vaccine or combination.
Analysis of the immune cells revealed a “marked increase” in CD3+, CD8+, and CD4+ T cells in the splenic marginal zones of the combination group, consistent with flow cytometry data. There was also an increase in B lymphocytes and follicular DCs in this group. For TILs, the combination therapy also increased the number of CD8+ and CD4+ T cells.
Improving outcomes
Despite therapeutic advancements, high-risk patients with MM “continue to have poor outcomes”, and there are limited agents to prevent MM or progression from MGUS and SMM. The results from the study suggest that PD1 blockade “enhances tumour growth inhibition” in mice treated with the DNA vaccine and highlight the potential of the DNA-based GPRC5D vaccine to “overcome self-tolerance and the prospects of advancing” into clinical trials.
For the latest on cancer vaccine development and combination approaches to disease control, join us at the Congress in Barcelona next week. Don’t forget to subscribe to our weekly newsletters for more vaccine updates.
by Charlotte Kilpatrick | Sep 19, 2024 | Therapeutic |
In September 2024, Brenus Pharma announced the completion of a $25 million Series A financing round and receipt of non-dilutive funding to take the STC-1010 cancer vaccine through proof-of-concept in first-line settings for metastatic colorectal cancer patients. STC-1010 is the first candidate based on Brenus Pharma’s STC (Stimulated Tumour (ghost) Cells) technology platform, which offers a new type of precision treatment for a “significant public health challenge”. The platform will be deployed in humans from the end of the year, beginning with STC-1010.
STC platform
Brenus Pharma’s STC platform is designed to educate the immune system to “recognise and anticipate escape mechanisms” in cold tumours. Four key stages happen after injection:
- APC (antigen-presenting cell) cross-priming activation
- TILs (tumour-infiltrating lymphocytes) pool generation
- TILs expansion
- Tumour cell destruction
The technology “not only treats the immediate threat, but also defends the immune system against tumours that may appear later”, reducing a risk of relapse. This is achieved through the education of a patient’s immune system through the “widest panel of therapeutic targets currently available”.
Trials
STC-1010 will be administered as a first-line treatment in patients with unresectable metastatic colorectal cancer (mCRC) resistant to immunotherapies. It will also be tested in other types of gastric tumours, including those of the pancreas and liver. The second candidate in development, STC-1020, will be developed in other solid tumour indications. The team is optimistic that the platform products can become a “permanent part of precision medicine”.
The Phase I/IIA study of STC-1010 is known as “BreAK-CRC”; it is under review by the European regulatory authorities in preparation for participation of clinicians in early-phase immuno-oncology units in Europe and the United States. Phase I will evaluate the tolerability of different dose levels, combined with low dose immunostimulants and standard chemotherapy. The Phase IIA study will evaluate treatment efficacy, with a focus on progression-free survival at 12 months.
Achieving ambitious goals
Jacques Gardette, Chair of BIOJAG, confirmed that “Brenus Pharma now has our full attention to help the company achieve its ambitious goals” as it takes a “major step forward”.
“The arrival of investment professionals in our young company confirms the interest we are arousing…I’m convinced that the constant commitment and innovation of the Brenus team have built a solid foundation for tackling one of the world’s most complex therapeutic challenges.”
Mr Gardette commented on the “boldness, achievement, and resilience” demonstrated by Brenus in its “rapid development”. Dr Paul Bravetti, CEO of Brenus Pharma, reflected that the investment interest is an “important milestone” that confirms the platform’s potential.
“I would like to thank all our team for their motivation and their passionate work to rapidly bring a new therapeutic solution to patients. Our shared ambition is to position our platform at the forefront of the national and international scene, and to become a leader in next-generation cancer immunotherapies.”
Marie Chambodut, Partner and Investment Director at Angelor, is “proud” to lead the strategic transaction.
“We look forward to joining Paul and his exceptional team in transforming Brenus into a global player in precision immuno-oncology, bringing solutions to millions of patients experiencing treatment failure, and contributing to the development of the French biotherapeutics industry.”
Investment Manager at Noshaq, Hélène Sabatal, is “delighted” to support the development of the “cutting-edge technological platform”.
“We are convinced of its future impact for patients currently without concrete therapeutic solutions.”
For the latest in cancer vaccine development and technology, join us at the Congress in Barcelona next month, and don’t forget to subscribe to our weekly newsletters here.
by Charlotte Kilpatrick | Sep 16, 2024 | Global Health |
In September 2024 WHO announced the establishment of an access and allocation mechanism for mpox medical countermeasures, including vaccines, treatments, and diagnostic tests. The Access and Allocation Mechanism (AAM) is intended to increase access to these essential tools for people at highest risk, ensuring that limited supplies are used “effectively and equitably”. This announcement comes after WHO declared the mpox outbreak a PHEIC in August 2024 and addresses one of the key International Health Regulations Emergency Committee’s recommendations: “equitable access to safe, effective, and quality-assured countermeasures”.
AAM
The AAM is part of the interim Medical Countermeasures Network (i-MCM-Net). Developed in response to “global vulnerabilities” exposed by the COVID-19 pandemic, i-MCM-Net enhances collaboration through a “Network of Networks” approach. It seeks to provide timely and equitable access to quality, safe, effective, and affordable medical countermeasures in response to public health emergencies through existing networks and global collaboration. The network was endorsed by WHO Member States as an interim mechanism while negotiations on a pandemic agreement continue.
The mpox AAM includes members of the i-MCM-Net as well as WHO: Africa CDC, CEPI, the EU Health Emergency Preparedness and Response Authority (HERA), FIND, Gavi, the PAHO Revolving Fund, UNICEF, Unitaid, and others. It will work to allocate the “currently scarce supplies” to those at highest risk of infection.
It will operate according to three guiding principles:
- Preventing illness and death – prioritise vaccination and other tools to interrupt transmission for those at greatest risk to prevent illness and death.
- Mitigating inequity – ensure equitable access to medical countermeasures for all people at risk, irrespective of socio-economic or demographic background.
- Ensuring transparency and flexibility – establish and maintain clear and open communication about allocation decisions and be ready to adapt strategies as new data emerge or situations change.
More than 3.6 million vaccine doses have been pledged for the mpox response, including 620,000 doses of MVA-BN pledged to affected countries by the European Commission, Austria, Belgium, Croatia, Cyprus, France, Germany, Luxembourg, Malta, Poland, Spain, and the United States of America, as well as Bavarian Nordic. Japan has pledged 3 million doses of the LC16 vaccine. This is the largest pledge so far.
International coordination
Dr Tedros Adhanom Ghebreyesus, WHO Director-General, recognised the need for “powerful tools” like vaccines, therapeutics, and diagnostics, to bring the mpox outbreak “under control”.
“The COVID-19 pandemic illustrated the need for international coordination to promote equitable access to these tools so they can be used most effectively where they are most needed. We urge countries with supplies of vaccines and other products to come forward with donations, to prevent infections, stop transmission, and save lives.”
Dr Mike Ryan, Executive Director of WHO’s Health Emergencies Programme, emphasised that WHO and its partners are working with the government of the Democratic Republic of the Congo and other affected countries to “implement an integrated approach to case detection, contact tracing, targeted vaccination, clinical and home care, infection prevention and control, community engagement and mobilisation, and specialised logistical support”.
“The AAM will provide a reliable pipeline of vaccines and other tools in order to ensure the success on the ground in interrupting transmission and reducing suffering.”
Join us at the Congress in Barcelona next month to share your insights on the best ways to ensure equitable access to essential medical countermeasures, and don’t forget to subscribe to our weekly newsletters for the latest vaccine news.
by Charlotte Kilpatrick | Sep 16, 2024 | Therapeutic |
In September 2024, IO Biotech announced “promising” data from its Phase II basket trial of IO102-IO103 in combination with Merck’s anti-PD-1 therapy KEYTRUDA (pembrolizumab). These results were shared in a conference presentation that included clinical and biomarker data from patients with recurrent or metastatic (advanced) squamous cell carcinoma of the head and neck (SCCHN) with PD-L1 CPS ≥ 20. The study met its primary endpoint and identified a safety profile consistent with prior studies.
IO102-IO103
IO Biotech’s lead product candidate is IO102-IO103, which combines two wholly owned T-win vaccines designed to “activate and expand” T cells specific for IDO and PD-L1. T-win is an immune-modulating vaccine technology that is directed against tumour cells and the “most important” immune-suppressive cells in the tumour microenvironment (TME). Many types of solid tumours and immune-suppressive cells (Tregs and TAms) in the TME overexpress IDO and/or PD-L1. Thus, the combination of the two vaccines is intended to “have a synergistic effect” that leads to “enhanced cell killing”.
The Phase II basket study is a non-comparative, open-label trial that investigates the safety and efficacy of a combination of IO101-IO103 with pembrolizumab as a first-line treatment in up to 60 patients with metastatic non-small cell lung cancer (NSCLC) with PD-L1 TPS ≥ 50% and recurrent or metastatic SCCHN with PD-L1 CPS ≥ 20. The primary endpoint is overall response rate (ORR).
Promising data
Data from 18 efficacy evaluable patients revealed:
- The achievement of the primary endpoint – confirmed 44.4% overall response rate (ORR) in a PD-L1 high population of patients with SCCHN irrespective of HPV status.
- An “encouraging” 6.6-month median progression-free survival (PFS).
- A 66.7% disease control rate (DCR).
- A safety profile that is consistent with previously reported data from a combination approach.
- The detection of T-cell responses to both IO102 (targeting IDO) and IO103 (targeting PD-L1) after treatment.
Dr Jonathan Riess, principal investigator of the trial and Director, Thoracic Oncology at UC Davis Comprehensive Cancer Centre, is encouraged by the data in support of the combination approach.
“Given the need for new treatment options that are effective, safe, and accessible for head and neck cancer patients, further investigation of this combination should be conducted to build on the findings of this Phase II trial.”
Chief Medical Officer of IO Biotech, Dr Qasim Ahmad described “accumulating” evidence that the combination could be a “safe and efficacious first-line treatment for patients with a range of cancers”. This includes those with metastatic and “difficult-to-treat disease”.
“Importantly, with mPFS of 6.6 months, more than half of the patients in this trial had over 180 days of progression-free survival. These data are supportive of further investigation of this combination regimen as part of our commitment to transform the lives of cancer patients through our novel therapeutic vaccine.”
For more cancer vaccine updates at the Congress in Barcelona next month, get your tickets to join us here, and don’t forget to subscribe to our weekly newsletters here.
by Charlotte Kilpatrick | Aug 30, 2024 | Therapeutic |
Research in Nature communications in August 2024 reports a non-human primate model of metabolic post-acute sequelae of SARS-CoV-2 to identify a dysregulated blood chemokine signature in acute COVID-19 that correlates with “elevated and persistent hyperglycaemia” four months post-infection. The authors also report a favourable glycaemic effect of the mRNA vaccine, administered on day 4 post-infection. This approach could help to address “one of the most concerning issues” of long-term health conditions after COVID-19 infection; hyperglycaemia can lead to health complications like diabetes and heart disease.
PASC or Long-COVID
The paper states that between 10% and 30% of people infected with SARS-CoV-2 develop long-term health complications, known as post-acute sequelae of SARS-CoV-2 (PASC) or Long-COVID. These complications fall along a “broad spectrum” from metabolic diseases to conditions with “less obvious metabolic undertones”. Evidence suggests a hyperinflammatory response is “critical” to the severity of acute COVID-19 and the development of metabolic PASC such as hyperglycaemia.
Although it is suggested that the balance between virus survival and effective host responses is based on the metabolic reprogramming of nutrients, the extent to which early disruptions in systemic immune and metabolic homeostasis contribute to metabolic PASC “remains unclear”. Furthermore, a “lack of appropriate animal models” for metabolic PASC means that the mechanisms by which SARS-CoV-2 infection “promotes prolonged hyperglycaemia” are “poorly understood”.
The study
The researchers developed a model using SARS-CoV-2 infected non-human primates (NHPs). African green monkeys (AGMs) were infected intranasally and intratracheally; blood biochemistry, virologic, and immunologic parameters were analysed longitudinally for an 18-week period. Metabolic, virologic, and clinical analyses were also performed on selected tissues at necropsy to “interrogate potential mechanisms that underlie the development” of metabolic PASC.
To explore if vaccination against SARS-CoV-2 during acute infection, prior to multiorgan distribution from the lungs, could elicit a “more favourable” tissue microenvironment that reduces the tissue burden of replication competent SARS-CoV-2 and/or viral fragments, the authors investigated administration of the BNT162b2 vaccine four days after infection. The cohort was split into two groups: unvaccinated (10) and vaccinated (5). The vaccinated group were vaccinated 4 days post infection with the mRNA vaccine BNT162b2.
Findings
The data demonstrate that SARS-CoV-2 infection of AGMs is “associated with early-onset hyperglycaemia”, persisting for at least 18 weeks post infection. However, the vaccination of five of the animals 4 days post infection was associated with a “consistent and significantly lower” blood glucose level over the study period. Dr Clovis Palmer, a lead author of the study, describes the research as a “new frontier in our fight against COVID-19″.
“By showing that the vaccine can have therapeutic benefits even after infection, we can explore new strategies to help those suffering from long-COVID, especially those with symptoms like chronic fatigue that may be linked to metabolic dysfunction.”
Dr Jay Rappaport, co-corresponding author and director of the Tulane National Primate Research Centre commented that the discovery that COVID-19 can “induce diabetes in an animal model” is a “significant advancement in our understanding of the long-term effects”.
“The fact that a COVID vaccine given after infection can have protective effects highlights the importance of innovative research in addressing the ongoing challenges of a pandemic.”
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by Charlotte Kilpatrick | Aug 23, 2024 | Therapeutic |
University College London Hospitals (UCLH) announced in August 2024 that a patient with lung cancer at UCLH is the first to receive a novel cancer vaccine in a clinical trial in the UK. BioNTech’s investigational immunotherapy, BNT166, uses mRNA to present common tumour markers from non-small cell lung cancer (NSCLC) to the patient’s immune system. The vaccine is designed to offer a lower risk of toxicity to health, non-cancerous cells. This study will determine if BNT116 is safe and well tolerated. It is enrolling patients at different stages of NSCLC.
The trial
The trial is intended to establish the safety profile and a safe dose of BNT116 as a monotherapy as well as BNT116 in combination with other treatments for NSCLC to explore if BNT116 has a “synergistic anti-tumour effect” in combination. Around 130 participants will be enrolled in the study at 34 research sites in seven countries; six sites in the UK have been selected.
Consultant medical oncologist Dr Sarah Benafif is leading the study at UCLH and stated that “the strength of the approach” is that the treatment is “aimed at being highly targeted towards cancer cells”.
“In this way we hope that in time we are able to show that the treatment is effective against lung cancer whilst leaving other tissues untouched.”
UCLH Director of Research and Director of the NIHR UCLH Biomedical Research Centre, Professor Karl Peggs emphasised that “developing new approaches to cancer is a major priority for research at UCLH and within the BRC”. Professor Peggs is excited to see the first-in-human research “get started” at UCLH.
“We are able to do this kind of research thanks to our first-rate clinicians and research teams, our track record of working alongside industry, and our facilities and infrastructure which receive crucial support from the NIHR.”
An exciting new era
Professor Siow Ming Lee of UCL reflected that lung cancer “remains the leading cause of cancer deaths worldwide”, causing an estimated 1.8 million deaths in 2020.
“We are now entering this very exciting new era of mRNA-based immunotherapy clinical trials to investigate the treatment of lung cancer, thanks to the foundation laid by the Office for Life Sciences, within the Department for Science, Innovation, and Technology and the Department for Health and Social Care.”
Professor Lee hopes that the research will “provide an opportunity to further improve outcomes for our NSCLC patients, whether in the early or advanced stages”.
Advancing science
The first participant in the trial is Janusz Racz, 67, from London. He decided to participate in the trail “because I hope it will provide a defence against cancer cells” but also because “my participation in this research could help other people in future and help this therapy become more widely available”.
“As a scientist myself, I know that science can only advance if people agree to participate in programmes like this. I work in artificial intelligence, and I am open to trying new things. My family did research about the trial too, and they supported me taking part.”
Science Minister Lord Vallance is pleased to see the vaccine taking its “next important step” with potential to save the lives of “thousands diagnosed with lung cancer every year”.
“With Government support, these trials demonstrate again that the UK’s world-leading life sciences sector is at the forefront of turning research into new treatments like cancer vaccines, which could be transformative for patients up and down the country. We back our researchers so that they can continue to be an integral part of projects that produce groundbreaking therapies, like this one.”
NHS England national cancer director Dame Cally Palmer believes that if this is successful, cancer vaccines could be “revolutionary in vaccinating people against their own cancers to prevent the cancer recurring after their initial treatment”.
“Pioneering work is being undertaken by hospitals throughout the country with their university and industry partners to look at ways of harnessing the body’s own immune system to treat a range of cancers.”
Although a cancer diagnosis is “very worrying”, access to trials and other interventions “provides hope”.
“We expect to see thousands more patients taking part in trials over the next few years.”
For more on cancer vaccine developments, including from representatives of BioNTech, join us at the Congress in Barcelona this October and don’t forget to subscribe to our weekly newsletters here.
by Charlotte Kilpatrick | Jul 31, 2024 | Infection |
Africa CDC shared a situation update on mpox on the African continent in July 2024. This reveals that between January 2022 and July 2024 a total of 37,583 cases and 1,451 deaths have been reported. The Case Fatality Rate (CFR) is 3.9%. 15 African Union Member States have reported these cases. In 2024 alone (until July 2024), a total of 14,250 cases and 456 deaths (CFR of 3.2%) have been reported from 10 Member States. This represents a 160% increase in cases and a 19% increase in deaths compared to the same period in 2023.
A worrying increase
Over the past two years the 15 Member States that have reported mpox cases are: Benin, Burundi, Cameroon, Central African Republic (CAR), Congo, Democratic Republic of Congo (DRC), Egypt, Ghana, Liberia, Morocco, Mozambique, Nigeria, Rwanda, Sudan, and South Africa. In 2024 the following countries have reported cases:
- Burundi – 8 cases, 0 deaths
- Cameroon – 35 cases, 2 deaths
- CAR – 213 cases, 0 deaths
- Congo – 146 cases, 1 death
- DRC – 13,791 cases, 450 deaths
- Ghana – 4 cases, 0 deaths
- Liberia – 5 cases, 0 deaths
- Nigeria – 24 cases, 0 deaths
- Rwanda – 2 cases, 0 deaths
- South Africa – 22 cases, 3 deaths
Further to these cases, Chad has reported 24 suspected cases but no confirmed cases. DRC accounts for 96.3% of all cases and 97% of all deaths in 2024.
High geoscope and risk
Africa CDC ranks the geographic scope (geoscope) for mpox in Africa as “high”. Considering the morbidity and mortality, probability of spread, and availability of effective control measures, the risk assessment is also “high”.
“While mpox is moderately transmissible and usually self-limiting, the case fatality rate has been much higher on the African continent compared to the rest of the world. Despite a safe and effective vaccine and antiviral treatment against mpox, these are not readily available.”
Africa CDC’s response
The update concludes with a few “key ongoing activities” contributing to Africa CDC’s participation in mpox preparedness and response:
- Activation of the Emergency Operations Centre (EOC) to enhance coordination and provide technical support to Member States
- High-level political advocacy and agenda setting
- Deployment of the Africa CDC Rapid Response Team to DRC to support response efforts including coordination, surveillance and contact tracing, field investigation, and strategy development
- Laboratory support – providing RT-PCR test kits and ancillary supplies and training participants in sample processing, RT-PCR-based detection, sequencing, and molecular diagnosis
- Training and resources – a four-module animated course for public health professionals, policymakers, and health workers in endemic areas with information on mpox prevention, detection, treatment, patient care, infection control, and outbreak investigation
- Collaboration with partners
- Advocating for strengthened surveillance, diagnostic capacities, and access to vaccines and medical drugs
For more on using available vaccines to control outbreaks across the world, why not join us in Barcelona for the Congress this October? Don’t forget to subscribe to our weekly newsletters here for infectious disease insights.
by Charlotte Kilpatrick | Jul 29, 2024 | Global Health |
On 28th July 2024 WHO marked World Hepatitis Day with the theme “it’s time for action”, calling for increased awareness of viral hepatitis. It stated that prevention, diagnosis, and treatment must be accelerated to address the tragedy of a death every 30 seconds from a hepatitis-related illness. Despite diagnosis and treatment innovation, alongside decreased product prices, WHO notes that “testing and treatment coverage rates have stalled”. However, it is hopeful that the 2030 elimination goal “should still be achievable, if swift action is taken now”.
Threat to the liver
Hepatitis is a liver inflammation that is “usually caused” by a viral infection or non-infectious agents like drugs, toxins, and alcohol. There are five main strains of the hepatitis virus (A, B, C, D, and E). They all cause liver disease, but types B and C combined are the “most common” cause of liver cirrhosis, loss of liver function, liver cancer, and viral hepatitis-related deaths. In 2022 they caused 1.3 million deaths, with around one hepatitis death every 30 seconds.
Around 220 million people with hepatitis B are undiagnosed, and nearly 36 million people with hepatitis C undiagnosed. As most symptoms emerge after the disease has advanced, many people only discover that they have hepatitis B or C when they develop serious liver disease or cancer. However, even after a diagnosis, coverage of treatment and care for people with hepatitis is “astonishingly low”.
WHO’s key messages
Under the World Hepatitis Day campaign WHO shared 4 “key messages”:
- A liver performs over 500 vital functions every single day to keep us alive. That’s why testing, treating, and preventing viral hepatitis is so important.
- Deaths from viral hepatitis-related causes are increasing.
- Globally, there’s a huge number of undiagnosed and untreated people living with hepatitis.
- So many hepatitis infections – and deaths – can be prevented.
- Reaching 2030 targets
WHO urges action to achieve the “ambitious targets” for 2030, suggesting that simplified care services for viral hepatitis should ensure that:
- All pregnant women living with chronic hepatitis B have access to treatment and their infants have access to hepatitis B birth vaccines to prevent infection
- 90% of people living with hepatitis B and/or hepatitis C are diagnosed
- 80% of diagnosed people are cured of hepatitis C or treated according to newer hepatitis expanded eligibility criteria.
Although there are tools and guidance to diagnose, treat, and prevent chronic viral hepatitis, these services are “still too often out of reach”. For example, rapid diagnostic tests for viral hepatitis cost less than US$2, but many people still face “out of pocket costs” for testing. Furthermore, despite the availability of affordable generic viral hepatitis medicines, too many countries overpay; medicines that are used to treated hepatitis C cost US$60 for a 12-week course, but countries can pay up to US$10,000.
Time to take action
WHO calls for action to prioritise testing, treatment, and vaccination to realise a hepatitis-free world and meet 2030 targets. Key actions include:
- Expanding access to testing and diagnostics to ensure more people can access the treatment they need
- Strengthening primary care prevention efforts to prevent hepatitis through vaccination, safe infection and injections practices, and education
- Decentralising hepatitis care to bring care closer to patients by utilising community-based services
- Integrating hepatitis care within existing healthy services, combining hepatitis treatment with primary care, HIV services, and harm reduction programmes where relevant to offer more accessible and comprehensive care
- Engaging affected communities and civil society, ensuring that the insights and experiences of people affected viral hepatitis are at the heart of prevention and treatment efforts
- Mobilising domestic or innovative financing to secure new funding avenues to support and sustain hepatitis elimination programmes.
ECDC marks World Hepatitis Day
The European Centre for Disease Prevention and Control (ECDC) also shared a statement addressing World Hepatitis Day 2024, focusing on the prevention of liver cancer. It states that chronic hepatitis is “among the main risk factors” for liver cancer, which is the sixth leading cause of cancer-related deaths in Europe; it accounted for nearly 55,000 deaths in 2022. Around 3.6 million people in the EU/EEA are chronically infected with hepatitis B virus (HBV) and hepatitis C virus (HBC), but infection prevalence and access to prevention and care “varies considerably”. A particularly high burden is identified in “vulnerable groups”, including people who infect drugs, people in prison, and some migrant populations.
ECDC calls for “enhanced efforts and collaboration between governments, healthcare providers, and communities, to accelerate progress”. It suggests that scaling up vaccination programmes, implementing targeted testing initiatives, ensuring systematic linkage to care, and enhancing infection prevention measures, we can “achieve a healthier future for all”. Dr Piotr Kramarz, ECDC Chief Scientist, demands intensified efforts.
“The power to prevent cancer is within our reach.”
For more on the management of infectious diseases and how vaccination strategies are critical to this endeavour, why not join us at the Congress in Barcelona this October, or subscribe to our weekly newsletters here?
by Charlotte Kilpatrick | Jul 8, 2024 | Therapeutic |
In July 2024, HOOKIPA Pharma announced that the first person has been dosed in a Phase Ib clinical trial of HB-500, an investigational therapeutic vaccine for the treatment of HIV. The trial is to evaluate the safety and tolerability, reactogenicity, and immunogenicity of repeated doses of HB-500 in participants with HIV on suppressive antiretroviral treatment. The arenaviral vaccine was developed in collaboration with Gilead Sciences, and the beginning of the trial ensures that HOOKIPA achieves a $5 million non-dilutive milestone payment through the collaboration and license agreement.
HB-500
HB-500 comprises two genetically engineered replicating vectors based on the arenaviruses Pichinde virus and lymphocytic choriomeningitis virus. The vectors have been engineered to deliver HIV antigens that have been derived from parts of “key, immunogenic regions” of HIV type 1 (HIV-1) proteins that are highly conserved in HIV-1 clade B variants. The designed immunogens differ by amino acid sequence to allow coverage of >80% of circulating HIV-1 viral variants.
HOOKIPA states that the adenovirus technology has “several key advantages” including:
- The ability to induce a robust CD8+ T cell response by directly targeting and activating dendritic cells
- The ability to induce a robust antibody response to disease-specific target antigens
- The possibility for repeat administration to boost immune response
- No need for an adjuvant to stimulate the immune system
- Demonstrated good tolerability in preclinical studies and clinical trials
The trial began with the first participant on 1st July 2024 and comprises two dose escalation cohorts that will be randomised to receive either HB-500 or placebo. Enrolment is ongoing. HOOKIPA takes responsibility for “advancing the HIV programme” through the completion of the Phase Ib clinical trial. Following this, Gilead has the exclusive right to assume further development of the programme.
Taking an important step
CEO of HOOKIPA, Joern Aldag, commented that HIV “impacts the daily lives of millions globally, with no known curative treatment”.
“While current treatments effectively block viral replication and can prevent progression to AIDS, they have not been shown to clear the virus from people living with HIV, requiring lifelong treatment.”
Aldag states that the team is “happy to have begun the Phase Ib trial” after “impressive findings” at the preclinical stage.
“Our team has worked tirelessly, alongside our great collaboration partners at Gilead, to reach this point, and we are excited to take in important step toward finding a curative treatment for HIV.”
For more updates on therapeutic vaccine efforts, don’t forget to subscribe to our weekly newsletters here.
by Charlotte Kilpatrick | Jul 3, 2024 | Therapeutic |
A report shared by WHO in July 2024 presents the importance of designing therapeutic human papillomavirus (HPV) vaccines for use in lower resource settings to ensure “maximum public health benefits”. WHO preferred product characteristics for therapeutic HPV vaccines provides guidance to encourage innovation and development of therapeutic vaccines to “clear or treat” HPV infections or HPV-associated precancers or cancers. The report outlines ideal “parameters” such as vaccine indications, target populations, safety and efficacy considerations, and immunisation strategies.
Another tool against HPV-related cancers
The report states that the development of therapeutic vaccines for human papillomavirus (HPV) could provide an “important addition” to current methods for the prevention and treatment of HPV-related cancers. This includes cervical cancer, which is caused “almost exclusively” by sexual transmission of oncogenic types of HPV and represents an “important public health problem globally”. In 2022, an estimated 662,000 women were diagnosed with cervical cancer, and approximately 349,000 women died from the disease.
WHO states that “over 90%” of cervical cancer-associated deaths were among women in low- and middle-income countries (LMICs), which is attributed to “inequitable access to effective cervical cancer prevention and management measures”. Efforts to eliminate cervical cancer as a public health problem will involve three key targets:
- Vaccination of 90% of girls with prophylactic HPV vaccines
- Screening of 70% of women for cervical cancer with a high-performance test twice in their lifetime
- Provision of treatment to 90% of women with cervical precancers and invasive cancers
However, progress towards elimination is lagging, with issues such as the “cost and complexity” of screening and treatment programmes and “persistent inequities in access”. Therefore, therapeutic HPV vaccines, currently in early clinical development, could offer an “additional tool” to address gaps in cervical cancer programmes.
Considerations for vaccine development
A group of experts explored the “feasibility, pipeline, and clinical development considerations” for future therapeutic HPV vaccines to meet public health needs. They focused on vaccines that “primarily clear high-risk HPV infection and/or cause regression of high-grade cervical precancers”.
Feasibility
The report states that all HPV types encode “early” proteins (E-proteins: E1, E2, E4-E7) and “late” virion structural proteins (L-proteins: L1, L2). Infection is caused when HPV virions bind to basal cells in the epithelium using the viral capsid protein L1, so current prophylactic HPV vaccines target L1. In infected cells, E1 and E2 proteins facilitate viral replication and transcription, while E6 and E7 proteins drive cell proliferation. E6 and E7 are the main targets of “most” therapeutic vaccine candidates to date. However, to target early stages of pathogenesis, including proteins like E1 and E2 could be “critical for successful termination of HPV infection and the prevention of precancer”.
There are several challenges for therapeutic HPV vaccine development. For example, it has a “relatively slow life cycle that is non-cytolytic, actively evades the innate and adaptive immune response, and does not induce a high level of inflammation that would alert the host to infection”. As antibodies are “insufficient to clear persistent HPV infection” or reduce precancerous lesions, post-exposure therapeutic vaccines will likely need to induce cell-mediated immunity with effective T cell responses against early viral proteins across genetically diverse populations.
Furthermore, advanced cervical lesions have often undergone immune selection and present a highly immunosuppressive local environment that poses “scientific and immunological challenges”. Thus, WHO suggests that it could be easier to develop efficacious therapeutic HPV vaccines that target HPV infection or low-grade precancerous lesions than vaccines that target high-grade precancers or invasive cervical cancer. The experts considered an effective single-dose vaccine “unlikely” for targeting persistent high-risk HPV infection or more advanced cervical disease.
“Mucosal delivery, such as oral or intravaginal, for either initial or booster dosing might improve the immune response and could allow self-administration. Intravaginal administration may have the added benefit of recruiting T cells into the relevant tissue site.”
Pipeline
Although there are no licensed therapeutic HPV vaccines, the pipeline is “active”, with a “wide variety of approaches” deployed, including peptide, protein, DNA, RNA, and bacterial- and viral-vectored vaccine platforms. Development has primarily focused on candidates targeting the regression of CIN2/3 lesions and invasive cervical cancer, but a few candidates target clearance of high-risk HPV infection. All candidates have been multiple-dose products administered at set intervals over several months, and the most common route of administration has been parenteral (subcutaneous and intramuscular) delivery. Other methods include oral delivery and direct injection at the site of the cervix.
Clinical development
Vaccine candidates designed primarily to clear HPV infection have not yet progressed to late-stage clinical development, with no specific regulatory pathways identified. Vaccine candidates designed primarily to cause regression of CIN2/3 lesions should be “carefully designed” to ensure they are “ethically and methodologically sound”. For both approaches, some outcomes could be evaluated post-licensure.
Preferred characteristics
WHO outlines several preferred characteristics in the report, divided into characteristics for vaccines used to clear oncogenic HPV infections, characteristics for vaccines used to treat cervical precancers, and characteristics common to both types of vaccines.
A catalytic innovation
Dr Sami Gottlieb, medical doctor and epidemiologist in WHO’s Department of Sexual and Reproductive Health and Research, commented on the importance of expanding access to existing interventions to eliminate cervical cancer as we advance the development of this tool.
“Therapeutic HPV vaccines could be a catalytic innovation to complement these efforts, increasing options for the millions of women who have already acquired HPV and reducing their risks of developing life-threatening cancer in the future.”
To read the report click here. For more on vaccine innovation and development, don’t forget to subscribe to our weekly newsletters here.
by Charlotte Kilpatrick | Jun 28, 2024 | Technology |
Researchers at La Jolla Institute for Immunology (LJI) Centre for Vaccine Innovation are exploring ways to prevent the fusion of measles “machinery” with host cell membranes. Using an imaging technique called cryo-electron microscopy, they have shown “in unprecedented detail” how an antibody can neutralise the measles virus before it completes fusion. Their work in Science (not open access) seeks to explain the mechanism of action of monoclonal antibody (mAb) 77, and could have implications beyond measles, such as for other members of the paramyxovirus family.
Measles concerns
Despite “extensive” vaccine efforts, measles remains a “major health threat”, particularly to children. Dr Erica Ollmann Saphire, LJI professor, states that the virus “causes more childhood deaths than any other vaccine-preventable disease” and is “one of the most infectious viruses known”. The study first author and LJI postdoctoral researcher Dr Dawid Zyla highlights that the risk is not just for young children.
“The current vaccine works well, but it cannot be taken by pregnant people or people with compromised immune systems.”
Furthermore, there is currently no specific treatment for measles.
mAb 77
An antibody called mAb 77 targets the measles fusion glycoprotein, which is the “piece of viral machinery” that enables the virus to enter human cells by fusion. Working with a team at Columbia University, the LJI team sought to engineer a version of the measles fusion glycoprotein that was stable enough for cryo-electron imaging. Dr Matteo Porotto, Professor of Viral Molecular Pathogenesis (in Paediatrics), had been exploring “strange mutations” in a measles variant that had targeted the central nervous system. This variant had weak points in the fusion glycoprotein structure that “forced” the virus to evolve.
“The virus has to mutate to go into the brain, but then it needs these stabilising mutations to compensate.”
Using this research, Dr Zyla could engineer a fusion glycoprotein with the same mutations; it could be mass produced and was “sturdy” enough for structural investigations. With the LJI Cryoelectron Microscopy Core, the researchers started to capture images that showed the fusion glycoprotein “in complex” with mAb 77. This revealed that mAb 77 “arrests the virus in the middle of the fusion process”, interrupting the “folding” towards fusion.
“It was striking to see what this intermediate step in the fusion process actually looks like.”
Dr Saphire agrees that it was “exciting” to capture “snapshots of the fusion process in action”.
“The series of images is like a flip book where we see snapshots along the way of the fusion protein unfolding, but then we see the antibody locking it together before it can complete the last stage in the fusion process. We think other antibodies against other viruses will do the same thing but have not been imaged like this before.”
Translating the research into treatment
With this newfound understanding of mAb 77, the researchers hope it could be used in a “treatment cocktail” for prevention or treatment of active measles infection. They found that mAb 77 offered “significant” protection against measles in cotton rat models, which were pretreated before virus exposure. The rats showed either no infection or “reduced signs of infection” in lung tissue.
However, the investigations will continue into different antibodies against measles. Dr Zyla states that “we’d like to stop fusion at different points in the process and investigate other therapeutic opportunities”. This can be done in collaboration with the team at Columbia University.
“The combination of structural biology expertise from LJI and cell biology and virology expertise from Columbia was key to pushing this project forward.”
Furthermore, this work could have implications for other viruses, such as Nipah, parainfluenza viruses, and Hendra viruses.
“These are all viruses with pandemic potential.”
We will explore the returning threat of measles at the Congress in Barcelona this October, so do get your tickets to join us there and don’t forget to subscribe to our weekly newsletters for more research updates.
by Charlotte Kilpatrick | Jun 3, 2024 | Therapeutic |
Transgene announced in June 2024 that the first patient has been enrolled in the Phase II part of a randomised Phase I/II clinical trial of TG4050 in the adjuvant treatment of head and neck cancer. Patient screening and enrolment are underway, with hopes of enrolling 80 patients internationally to continue the trial after Phase I data showed immunogenicity and first signs of clinical benefit. TG4050 is based on Transgene’s myvac viral vector platform and NEC’s cutting-edge AI capabilities for the identification and prediction of the most immunogenic neoantigens for every patient.
“TG4050 is the only individualised neoantigen cancer vaccine currently being developed in a randomised trial in the adjuvant treatment of head and neck cancer.”
The vaccine shows promise
Transgene states that “promising” data from Phase I showed “strong immunogenicity” and a “persistent cellular immune response” as well as “signs for clinical benefit for patients”. At the time of analysis all patients who received TG4050 were disease-free. Therefore, Transgene and partner NEC are moving into an extension of the randomised trial.
The Phase II will continue investigating single-agent TG4050 in patients with newly diagnosed, locoregionally advanced, HPV-negative, squamous cell carcinoma of the head and neck (SCCHN) in the adjuvant setting following completion of surgery and chemoradiotherapy. The international, multicentre, open label, two-arm trial is screening patients in Toulouse and Paris, in France, with other sites to be added in Europe and the US in the coming months.
A significant medical need
Despite advancements in the treatment of SCCHN, Transgene identifies a “significant medical need” for patients, including in the adjuvant setting. With the current standard of care, 30% to 40% of patients are expected to relapse within 24 months after surgery and adjuvant therapy. Dr Maud Brandely, Chief Medical Officer of Transgene, described the inclusion of the first patient as a “further milestone” for the company.
“In the ongoing trial, TG4050 is targeting patients with head and neck cancer at high-risk of relapse, with the aim of extending disease-free survival. The Phase I data we have generated indicate that TG4050 enables the induction of specific cellular immune responses that persist up to 7 months post treatment initiation, with all treated patients remaining disease-free after a median follow-up of 18.6 months.”
Dr Brandely is “encouraged” by the “promising clinical outcomes” and looks forward to generating more data.
“Personalised cancer vaccines are an extremely exciting development and, if successful, could also be utilised to treat other forms of cancer to improve and extend the lives of patients.”
For more on vaccine strategies for cancer treatment, why not join us in Barcelona for The World Vaccine Congress or subscribe to our weekly newsletters here?
by Charlotte Kilpatrick | May 20, 2024 | Infection |
The UKHSA shared guidance and information on cryptosporidium in May 2024 following South West Water’s acknowledgement that “small traces” of the parasite were identified in Brixham, south Devon. The water company is investigating the source of the outbreak, with 46 cases of cryptosporidiosis already confirmed. The company issued a boil water notice to residents as 46 confirmed cases were reported and over 100 people contacted their GPs about symptoms. The “microscopic” parasite causes cryptosporidiosis, which is “unpleasant” and “sometimes dangerous”.
What is cryptosporidium?
Cryptosporidium is a “nasty bug” that resides in the intestines of infected humans and animals. It is passed out in poo, when it can spread and contaminate water sources and food. It causes cryptosporidiosis, which is particularly common in young children, people who work with farm animals and contaminated waters, people changing nappies, and those who travel to countries with “poor sanitation”. It can cause “serious illness” in people with weakened immune systems.
Symptoms are “deeply unpleasant”, including severe watery diarrhoea, vomiting, stomach cramps, nausea, fever, or loss of appetite. It can last around 2 weeks. Prevention relies on “simple hygiene” steps, as there is no vaccine:
“The development of partial immunity after exposure suggests the possibility of a successful and effective vaccine, but protective surrogates are not precise.”
There is also no treatment, but rehydration is recommended after diarrhoea.
Outbreak in Devon
In May 2024 the BBC reported that South West Water (SWW) had suggested that a “faulty valve” may have created a route for the parasite into the water network. Laura Flowerdew, chief customer officer emphasised that the team is “doing further work to make sure we’re absolutely confident that’s the cause and the only cause”.
“We’re working through operational procedures in the meantime…public health is our absolute priority at this point.”
However, Anthony Mangall, MP for Totnes and South Devon, was “very concerned” with the response to the outbreak, suggesting that they had been “slow to act” and displayed “poor” communication with customers.
Expert opinion
Professor Paul Hunter from the University of East Anglia (UEA) commented that “in people with severely weakened immune systems it can cause severe disease and can even be fatal”. He suggested that “before effective antiretroviral treatments” for HIV/AIDS, cryptosporidium could be “fatal as recovery didn’t happen”.
“With effective control of AIDS nowadays we see far less severe cryptosporidiosis. There is no effective drug treatment for cryptosporidiosis and all we can do is keep people comfortable and replace fluids until recovery happens.”
Professor Hunter believes that there are “far fewer outbreaks now” than in the 1990s when he was “more involved” thanks to “improvements in treatment plants”. However, without regular summaries from UKHSA it is hard to know how many outbreaks have occurred.
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by Charlotte Kilpatrick | Feb 22, 2024 | Therapeutic |
In February 2024 UC Davis Health announced the results of a study, published in Advanced Science, which show that a single dose of the tuberculosis vaccine Bacillus Calmette-Guérin (BCG) reduced liver tumour burden and extended the survival of mice with liver cancer. BCG is known for “immune-boosting properties”, but this trial found that it could be a “promising treatment option” for hepatocellular carcinoma (HCC), which is often “associated with unfavourable treatment outcomes”.
HCC: significant challenges
The study describes hepatocellular carcinoma (HCC) as a “common” liver cancer that causes “numerous deaths” globally. Although conventional systemic cytotoxic chemotherapeutic agents, protein kinase inhibitors, and immunotherapy options exist, HCC “continues to pose significant challenges in terms of treatment”. Therefore, the authors identify a “pressing need” for alternative therapeutic approaches.
Distinguished Professor Yu-Jui Yvonne Wan, vice chair for research in the Department of Pathology and Laboratory Medicine at UC Davis, commented that “HCC is very difficult to treat”. It is “considered a cold tumour, which does not respond well to immunotherapy”. However, Professor Wan’s team had “a good reason to believe that the BCG vaccine could stimulate an immune response”.
BCG
BCG, derived from live attenuate Mycobacterium bovis, has been used as the primary tuberculosis vaccine since the 1920s. Although it has specific effects against tuberculosis, it has “non-specific effects”. These could be attributed to trained immunity.
BCG was approved by the FDA for the treatment of non-muscle invasive bladder cancer, which involves the administration of BCG directly into the bladder. However, there is “limited information available regarding the potential therapeutic effect of BCG” in the treatment of other solid tumours. Therefore, authors conducted a study to investigate the anti-HCC effects of BCG in orthotopic HCC mouse models.
A positive response
The researchers found that BCG reduced inflammation and encouraged the deployment of T cells, specifically allowing the infiltration of CD4+ and CD8+ T cells and M1 macrophages into the tumour. BCG also induced IFN- γ signalling, which resulted in cancer cell death. Furthermore, Professor Wan states that “while previous studies have shown sex differences in BCG effects on immunity”, the data indicate that “both male and female HCC mice responded to the BCG treatment”.
“Our study showed that BCG immunotherapy for HCC is different from and superior to other immunotherapies. It requires only a single injection. In animal models, BCG generated better anti-liver cancer treatment outcomes than other standard immunotherapies, such as anti-PD-1.”
The authors conclude that the study offers “compelling evidence” in support of BCG treatment for HCC. Additionally, because it is “widely used with a known safety profile”, BCG bacterial immunotherapy “should be considered for HCC as well as other solid cancers”.
For more on innovative uses of vaccines in cancer therapy don’t forget to get your tickets to the Congress in Washington or subscribe to our newsletters here.
by Charlotte Kilpatrick | Feb 5, 2024 | Therapeutic |
On 4th February 2024 World Cancer Day took place with a global call to action that marked the end of the “Close the Care Gap” campaign, 2022-2024. This year the World Cancer Day 2024 Equity Report was released with “local perspectives and experiences on inequities in cancer care” and “expert recommendations on how to address them”. World Cancer Day is a global initiative driven by the Union for International Cancer Control (UICC) that seeks to raise awareness, share knowledge, and consolidate action to “reimagine a world where millions of cancer deaths are prevented” and access to life-saving treatment is “equitable for all”.
“Who you are and where you live should not determine if you live.”
What is the care gap?
UICC states that “half the world’s population lacks access to the full range of essential health services”, a situation that has “only worsened” with the COVID-19 pandemic, which meant that “more than half a billion people” were pushed further into extreme poverty due to health care costs. Thanks to “awe-inspiring” advances, many cancers now have much better survival rates, yet for many people access to “adequate cancer care” is limited. This is known as the “equity gap”.
“While inequity is often measured in terms of the unequal distribution of health or resources, there are generally underlying and additional factors that contribute to this situation. These are known as the ‘social determinants of health’.”
Social determinants of health include education, cultural context, and gender norms.
“Health equity will be achieved when every person has the opportunity to reach his or her full health potential without barriers or limitations created by socioeconomic situation, discrimination or other socially determined circumstances.”
Professor Jeff Dunn AO, President of UICC, is glad that the report “shines a light on the barriers to care and significant disparities in outcomes”.
“More importantly, it provides local insights into the challenges we face in diverse regions, guiding us toward targeted solutions.”
Secretary-General of the Swedish Cancer Society and President-elect of UICC is Ulrika Årehed Kågström, who commented that “for people with low socioeconomic status, the risk of dying from cancer is generally notably higher” than for those who “belong to more privileged groups”.
“People with higher education generally spend more time with healthcare professionals to ask questions when seeking care than those with only primary school education, who are more likely to refrain from care-seeking in the first place. Socioeconomic status can also influence the degree to which a cancer patient is likely to follow through on treatment.”
How can we “close the gap”?
The report provides nine general recommendations to governments to support efforts to bridge the gap:
- Foster patient-centred care that acknowledges the unique needs of all patient populations, encouraging patient engagement in their care decisions.
- Increase funding for cancer research and encourage collaboration between researchers, healthcare providers, and community organisations to understand and address disparities.
- Establish a population-based cancer registry to guide policy decisions and resource allocation and evaluate control strategies.
- Implement an effective national cancer strategy based on an evidence-based assessment of the countrywide cancer burden, addressing financial hardship and barriers faced by underserved populations.
- Incorporate comprehensive cancer services into national health benefit packages to achieve universal health coverage.
- Enhance health literacy and education around cancer, using culturally appropriate materials and training for healthcare providers on effective patient communication.
- Regulate the production, sales, and marketing of carcinogenic products (tobacco, alcohol, ultra-processed foods) through increased taxation, marketing limitations, improved product labelling, and public education campaigns.
- Implement routine screening programmes for common cancers, integrate them into existing healthcare programmes, and utilise telemedicine services and mobile units to reach remote populations. The earlier a cancer is detected, the more successfully it can be treated and the less it costs to the health system.
- Address the systemic social determinants of health that impede an individual’s ability to access cancer care, tackling prejudices and assumptions based on diverse social markers.
How might vaccination contribute to closing the gap, or what should vaccine developers do to ensure that their efforts align with global gap-closing progress? Some of these questions will be explored at the Congress during our cancer and immunotherapy track, so do get your tickets to join us there! Until then, why not subscribe for more on health challenges and solutions?
