45 SARS-CoV-2 vaccine candidates are in clinical trials
Several vaccine candidates are close to completing clinical trials less than one year since the start of the COVID-19 pandemic. The inactivated vaccine CoronaVac (Sinovac), which reported safety in preliminary Phase 3 results from 9,000 volunteers in Brazil, is already being offered in China under emergency-use authorization.
The U.S. Food and Drug Administration (FDA) advisory group has dismissed the emergency use of experimental vaccines due to concerns that it might undermine the public’s trust in vaccines and hinder the development of other vaccines.
Further caution has been raised about adenovirus 5-vectored vaccines, including two in Phase 3 trials, as this vector had been found in previous clinical studies to increase the risk of contracting HIV in uncircumcised Ad5-seropositive men.Citation1
The development of two advanced vaccines, the adenovirus-vectored Ad26.COV2.S (J&J) and ChAdOx1-S (AstraZeneca), briefly stumbled after reports of serious adverse events, but resumed Phase 3 testing following investigation by U.S. authorities.
Passive immunization is an option for severely ill patients. A cocktail of two antibodies, REGN-COV2 (Regeneron), reduced symptoms and viral loads, but the Phase 2/3 trial stopped enrolling subjects in the most serious condition, after an independent committee saw an unfavorable safety profile.
We invite our Readers to explore the Special Focus on SARS-CoV-2 / COVID-19 vaccines and immunotherapies published in this issue of HV&I.
Combination immunotherapy approved for pleural mesothelioma
The FDA has approved the tandem immunotherapy of the PD-1 inhibitor nivolumab (Opdivo, BMS) and the CTLA-4 inhibitor ipilimumab (Yervoy, BMS) as first-line treatment in adults with unresectable malignant pleural mesothelioma. The decision is based on the Phase 3 Checkmate 743 trial, which showed 41% overall survival rate after two years for the combination, compared to 27% for standard-of-care chemotherapy.
Malignant pleural mesothelioma, which is often caused by exposure to asbestos, is a rare but aggressive cancer with five-year survival of less than 10%. Most cases are diagnosed late in advanced stages of the disease.
PCV-20 was safe and immunogenic in a Phase 3 trial
The 20-valent pneumococcal conjugate vaccine (PCV, Pfizer) was non-inferior to two marketed vaccines in vaccine-naïve adults. PCV-20 was tested against PCV-13 (Pfizer) and 23-valent polysaccharide vaccine (Merck) in subjects ≥60 years old as the primary endpoint, and its immunogenicity was compared between this age cohort and 18-59 year-olds as the secondary endpoint.
The Phase 3 trial, which involved 900 adults, reported robust immune responses against all 20 serotypes one month post-vaccination and acceptable safety with no serious adverse events. License application to FDA has been submitted.
Tralokinumab was safe in clinical trials with atopic dermatitis patients
The IL-13 inhibitor tralokinumab (LEO Pharma) demonstrated safety comparable to placebo in a pooled analysis of Phase 2 and 3 trials involving >2,000 subjects with atopic dermatitis. Most adverse events were moderate or mild during a one-year study period. Tralokinumab was associated with a higher rate of conjunctivitis and lower S. aureus colonization in lesional skin, and treatment had no effect on responses to Tdap vaccination.
Atopic dermatitis is a chronic inflammatory disease characterized by dysfunctional type 2 immune signaling. It is associated with eczematous lesions and itchiness of the skin.
RSV vaccine candidate was safe and immunogenic in healthy women and elderly
The RSV vaccines GSK3888550A and GSK3844766A (both GSK) were well tolerated and elicited robust antibody responses in two Phase 1/2 trials. The vaccines, designed for maternal immunization and older adults, respectively, are based on the recombinant subunit pre-fusion RSV antigen RSVPreF3. GSK3844766A is further adjuvanted with the AS01 system.
Different dosage levels were tested against a placebo in 500 healthy non-pregnant women and 1,000 healthy adults aged 60-80 years.
The vaccines are intended to protect the most vulnerable populations from RSV, which accounts for >30 million cases and >100,000 deaths in young children annually.
New 24-valent pneumococcal vaccine was safe and immunogenic in early trial
The pneumococcal vaccine candidate ASP3772 (Affinivax) was safe and well tolerated in adults up to 64 years old enrolled in a Phase 1 trial in the U.S. The vaccine is based on the multiple antigen-presenting system technology, which integrates polysaccharides and proteins in the same construct. ASP3772 targets 24 S. pneumoniae serotypes and two additional conserved proteins.
In addition to safety, ASP3772 demonstrated robust immunogenicity to all 24 serotypes. The vaccine is being evaluated in toddlers and elderly in separate trials.
Bone marrow-targeting nanobiologic might improve checkpoint inhibition immunotherapy
Inducing the so-called ‘trained immunity’ demonstrated antitumor efficacy and potentiated checkpoint inhibition immunotherapy in a preclinical studyCitation2. The biologic MTP10-HDL combines bone marrow-targeted nanomaterial with a drug that epigenetically modifies myeloid progenitor cells, leading to reversal of the immunosuppressive nature of tumor microenvironment.
MTP10-HDL improved outcomes of checkpoint inhibition immunotherapy in a mouse model of melanoma resistant to PD-1 or CTLA-4 blockade, and showed safety in non-human primates.
Universal influenza vaccine fails in late-stage clinical testing
The universal influenza vaccine candidate M-001 (BiondVax) failed to reduce the rate and severity of illness compared to placebo in a randomized double-blind Phase 3 trial. >12,000 adults aged ≥50 years were enrolled in Eastern Europe and monitored over one season. M-001 is designed to prevent infection by both influenza A and B by fusing nine epitopes in one recombinant protein.
References
- Buchbinder SP, McElrath MJ, Dieffenbach C, Corey L. Use of adenovirus type-5 vectored vaccines: a cautionary tale. Lancet 2020; 396(10260):e68-e69
- Priem B, van Leent MMT, Teunissen AJP, Sofias AM, Mourits VP, Willemsen L, Klein ED, Oosterwijk RS, Meerwaldt AE, Munitz J, Prévot G, Vera Verschuur A, Nauta SA, van Leeuwen EM, Fisher EL, de Jong KAM, Zhao Y, Toner YC, Soultanidis G, Calcagno C, Bomans PHH, Friedrich H, Sommerdijk N, Reiner T, Duivenvoorden R, Zupančič E, Di Martino JS, Kluza E, Rashidian M, Ploegh HL, Dijkhuizen RM, Hak S, Pérez-Medina C, Bravo-Cordero JJ, de Winther MPJ, Joosten LAB, van Elsas A, Fayad ZA, Rialdi A, Torre D, Guccione E, Ochando J, Netea MG, Griffioen AW, Mulder WJM. Trained Immunity-Promoting Nanobiologic Therapy Suppresses Tumor Growth and Potentiates Checkpoint Inhibition. Cell 2020; 183(3):786-801.e19