Human Vaccines & Immunotherapeutics: news

Multiple COVID-19 vaccines show high efficacy in clinical development of unprecedented pace

The U.S. Food and Drug Administration (FDA) has approved the monoclonal antibody bamlanivimab (LY-CoV555, Eli Lilly) for treatment of COVID-19 in subjects ≥12 years old at risk of progressing to severe disease or hospitalization. In a mid-stage clinical trial, bamlanivimab, whose sequence had been isolated from a patient after successful recovery, reduced the risk of an emergency-room visit to 3% compared to 10% in the placebo group.

Countries around the world are entering into agreements with pharma and biotech companies to secure millions of doses of investigational SARS-CoV-2 vaccines, which are close to emergency-use regulatory approval in the U.S. only one year after the emergence of the virus. Two candidates proved to be >90% efficacious in trials involving tens of thousands of people.

Two vaccines are based on mRNA delivery and in vivo expression of the antigen. The mRNA-1273 vaccine (Moderna) was shown to be 94% efficacious in preventing the disease according to interim results of Phase 3 data involving 30,000 subjects and 196 total infections. While the placebo group saw 30 severe cases, there were no severe cases in the experimental group. mRNA-1273 remains stable for a month at 4°C, which is important for delivery to remote areas with insufficient infrastructure.

Another mRNA vaccine, BNT162b1 (Pfizer & BioNTech), reported 95% efficacy, including in the elderly. The placebo-controlled Phase 3 trial has enrolled 43,000 volunteers, and there were 162 cases in the final analysis. The vaccine needs to be stored at -70°C until the time of delivery; the company is working on a pulverized formulation as a follow-on.

A non-replicating ChAdOx1-S vaccine (AstraZeneca) was 62-90% effective according to preliminary results of a Phase 3 trial with 10,000 individuals. Interestingly, the highest protection rate of 90% was reported for a cohort that received a lower first dose and full second dose, compared to 62% for two full doses. It remains to be determined whether the observation has medical significance.

While there is a great public health need for rapid deployment of COVID-19 vaccines globally, scientists worry that too rapid a deployment might compromise ongoing clinical trials and the determining of long-term vaccine-associated effects, because of demands to transfer subjects from placebo to the experimental group.

Two personalized cancer vaccines progress through clinical trials

The dendritic cell vaccine AV-GBM-1 (Aivita Biomedical) improved progression-free survival (PFS) in 57 patients with newly diagnosed glioblastoma in a single-arm Phase 2 study. PFS was 10 months for study subjects compared to 7 months in a previous study with standard-of-care treatment. AV-GBM-1 consists of autologous dendritic cells loaded with antigens from patients’ self-renewing tumor-initiating cells. The procedure up to therapeutic injections was successfully completed in 94% of attempted cases.

The peptide vaccine PGV-001 was well tolerated in patients with various solid and hematologic cancer types in a Phase 1 trial. PGV-001 protocol consists of DNA and RNA sequencing of tumor material and identifying most promising neoantigens by machine learning. Up to ten recombinant peptides are administered with the poly-ICLC adjuvant in two doses. Immunogenicity was confirmed for 7 peptides in one patient out of 15 trial participants.

Plant-derived influenza vaccine was safe and moderately protective in two large trials

A recombinant quadrivalent virus-like particle vaccine (Medicago) produced in the Australian tobacco plant was safe in two Phase 3 studies conducted during the northern 2017-9 seasons.¹ The first one compared the vaccine to placebo in 10,000 healthy subjects aged 18-64 years. It demonstrated safety and efficacy of ~40%, therefore failing to meet its primary endpoint of 70% efficacy.

In the second trial, 13,000 healthy adults 65+ years old were randomized to receive the investigational vaccine or a licensed quadrivalent inactivated vaccine. The plant-derived vaccine was non-inferior in terms of both safety and efficacy.

Combination immunotherapy benefited angiosarcoma patients

Treatment with two checkpoint inhibitors, the anti-PD-1 nivolumab (Opdivo, BMS) and anti-CTLA-4 ipilimumab (Yervoy, BMS), shrank tumors in four of 16 previously treated angiosarcoma patients enrolled in a Phase 2 trial. 12 subjects experienced adverse events, four of them severe adverse events.

Angiosarcoma is a rare tumor of blood or lymph vessels, which often metastasizes to liver or lungs. This clinical trial is a part of the DART series of studies, which tests the combination immunotherapy in various rare cancers.

Phase 3 testing commenced for a maternal RSV vaccine

The RSV vaccine candidate GSK3888550A (GSK) has entered a double-blind Phase 3 trial with up to 10,000 pregnant women aged 18-49 years. The vaccine, which had a good safety and immunogenicity profiles in non-pregnant women, contains a recombinant pre-fusion antigen of the RSV F protein. It is designed to protect infants through maternal immunization.

RSV is the leading cause of bronchiolitis and viral pneumonia in infants with 1.4 million annual hospitalizations globally. >30 million cases of RSV infection affect children <5 years every year.

Prostate cancer vaccine received FDA’s fast-track designation

The FDA has granted the fast-track designation to the prostate cancer vaccine RV001 (RhoVac), which is being evaluated in a Phase 2b trial in 175 patients. RV001 is designed to prevent metastases by targeting RhoC, which helps cancer cells metastasize by remodeling the extracellular matrix of the tumor microenvironment.

There are few treatment options for prostate cancer patients whose tumors recurred after first-line therapy. As RhoC facilitates the spread of various cancer types, RV001 can be explored outside prostate cancer, too.

Pembrolizumab was approved for triple-negative breast cancer

The FDA has approved the PD-1 inhibitor pembrolizumab (Keytruda, Merck) in combination with chemotherapy for treatment of unresectable, locally advanced or metastatic, PD-L1-positive triple-negative breast cancer. The decision is based on a Phase 3 study, which demonstrated the superior effect of the combination compared to chemotherapy alone.

New quadrivalent meningococcal conjugate vaccine approved in EU

The European Commission has approved the quadrivalent meningococcal conjugate vaccine MenQuadfi (Sanofi) for adults and children from one year of age. MenQuadfi proved to be safe and immunogenic in clinical trials involving >6,000 people.

The vaccine consists of polysaccharides from meningococcal serogroup A, C, Y and W, each conjugated to tetanus toxoid. It was previously approved in the U.S. for use in subjects ≥2 years old.

Immune checkpoint-targeting vaccine inhibits tumor growth in a colon cancer model

A recombinant PD-1 vaccine PD1-Vaxx in combination with a HER2-targeting vaccine B-Vaxx induced complete responses in 9 out of 10 mice with HER2-expressing colon cancer.² PD1-Vaxx consists of a PD-1 peptide linked to a measles virus fusion peptide.

“First, PD1-Vaxx activates both B- and T-cell functions to promote tumor clearance. Second, the treatment is targeted to block signaling pathways that are crucial for tumor growth and maintenance. By giving this vaccine in combination with an immunotherapy drug, we are essentially super-charging and specifically directing the immune system to target and kill cancer cells,” lead author Pravin Kaumaya of Ohio State University said.

PD1-Vaxx, which received FDA’s investigational new drug designation, is set to start a Phase 1 trial in patients with non-small cell lung cancer.