COVID-19 vaccines in clinical development
Almost 200 vaccines against SARS-CoV-2 are being developed, according to the World Health Organization. 40 are in clinical trials, of which ten have advanced to Phase 3.
Testing of one of the leading candidates, the non-replicating ChAdOx1-S vaccine (AstraZeneca), briefly stumbled after a participant reported a serious adverse event. However, all four Phase 3 trials resumed shortly thereafter.
Interim results from a Phase 3 trial with the mRNA vaccine BNT162b1 (Pfizer & BioNTech) showed a mild to moderate safety profile with adverse events consisting mostly of fatigue and headache. However, there were several severe adverse events after the second dose.
In addition to vaccines, the antibody LY-CoV555 (Eli Lilly) improved outcomes in a Phase 2 trial involving 450 subjects with mild COVID-19 infection. <2% of patients receiving the recombinant antibody, originally isolated from a patient who recovered from the disease, had to be hospitalized, compared to 6% in the placebo cohort.
70% of Americans are willing to get a COVID-19 vaccine, when one becomes available, according to a survey among 2,000 adults.Citation1 The lowest rate of only 55% was registered in the Black American community. “Given the disproportionate burden of COVID-19 infection and death among Black Americans, it’s concerning to see that Black survey participants had less interest in a vaccine,” lead author Paul Reiter of Ohio State University said.
Avelumab brings survival edge to bladder cancer patients
The PD-L1 inhibitor avelumab (Bavencio, Pfizer & Merck) added to supportive care increased overall survival at 1 year to 70% compared to 60% for supportive care alone in patients with unresectable locally advanced or metastatic urothelial carcinoma without disease progression after platinum chemotherapy.Citation2 Median overall survival was 21 and 14 months, respectively.
The Phase 3 Javelin Bladder 100 trial, which enrolled 700 subjects, showed a slightly higher rate of adverse events following avelumab treatment.
PCV-15 is ready for regulatory application after positive results of two large trials
The 15-valent pneumococcal conjugate vaccine V114 (Merck) met objectives in two Phase 3 trials involving healthy adults 50 years or older. In the randomized double-blind PNEU-AGE study with 1,200 study subjects, V114 proved non-inferior to the marketed 13-valent vaccine Prevnar 13 (Pfizer) and immunogenic for the two strains not targeted by this vaccine. V114 also elicited higher antibody responses to serotype 3, which is the leading global cause of invasive pneumococcal disease. The second PNEU-TRUE trial V114 showed high immunogenicity to all 15 serotypes and lot-to-lot consistency in 2,300 people.
V114 consists of pneumococcal polysaccharides conjugated to the mutant diphtheria toxin CRM197. Regulatory application is expected in late 2020.
BCG vaccine has protective effect against infectious diseases in the elderly
The BCG vaccine decreased incidence of infectious diseases in the elderly in the Phase 3 ACTIVATE trial.Citation3 200 subjects were vaccinated with BCG or placebo at hospital discharge and followed for one year. 25% of people in the experimental group developed an infection, compared to 42% in the placebo group. In addition, median time to first infection was 16 and 11 weeks, respectively. BCG, which is ordinarily given to children to protect from tuberculosis, has an overall activating effect on the immune system
“In addition to the clear effect of BCG vaccination on infections in general, the most important observation was that BCG could mainly protect against respiratory infections: BCG-vaccinated elderly people had 75% fewer respiratory infections than the elderly who received placebo,” lead author Evangelos Giamarellos-Bourboulis of University of Athens said.
Ipilimumab beneficial for prostate cancer patients
The CTLA-4 inhibitor ipilimumab (Yervoy, BMS) improved long-term survival in patients with metastasized, castration-resistant prostate cancer.Citation4 In the randomized Phase 3 CA184-043 trial, 800 subjects received ipilimumab or placebo following radiotherapy. Yearly follow-up to up to 5 years showed a 2- to 3-fold survival advantage in the ipilimumab cohort.
Prostate cancer is the second most common cancer in men and fifth leading cause of cancer death globally.
Pertussis vaccine candidate was safe and protective in a mid-stage trial
The live-attenuated pertussis vaccine BPZE1 (ILiAD) prevented 90% of nasal colonization and surpassed the licensed acellular vaccine Boostrix (GSK) in a Phase 2b trial with 300 healthy adults. The subjects were randomized to receive either of the two vaccines and challenged with BPZE1 or placebo 3 months later.
BPZE1, which is developed as a booster vaccine, was safe with no serious adverse events reported. Persistence of immune responses was confirmed at the end of the study 9 months after vaccination.
Blocking TGF-β1 signaling overcomes tumor resistance to anti-PD-1 immunotherapy in mice
Disabling TGF-β1 production induced immune-mediated rejection of mouse tumors otherwise resistant to checkpoint blockade immunotherapy.Citation5 The cytokine, which is produced by regulatory T cells, has been implicated in cancer progression and resistance to immune-activating therapies.
The mAb used in the study immobilizes TGF-β1 on the cell surface in an inactive state. Its addition to a PD-1 inhibitor increased the rate of tumor rejection and survival up to 5-fold in a mouse model of colon cancer.
Typhoid conjugate vaccine is safe an immunogenic in young children
The typhoid fever vaccine Vi-DT (International Vaccine Institute) was well tolerated and immunogenic in children aged 6-23 months in a Phase 2 trial.Citation6 Both one- and two-dose regimens induced comparable seroconversion rates. The vaccine consists of the Vi polysaccharide from Salmonella Typhi conjugated to diphtheria toxin.
Typhoid fever is a water-borne infection that causes an estimated 150,000 deaths annually, and especially affects children under 5 years of age in resource-limited countries.
Combination of CAR T-cell therapy and oncolytic viruses for treatment of solid tumors
The chimeric antigen receptor (CAR)-T cell therapy combined with an oncolytic vaccinia virus promoted tumor infiltration by immune cells and tumor control in several mouse models of solid cancers.Citation6 CAR-T cells specific for the B-cell antigen CD19 have been effective against blood cancers, but not against solid tumors. Thus, the oncolytic virus CD19t introduces this antigen into malignant cells and induces its expression. The CAR-T cells as well as endogenous T cells are then better able to infiltrate and eliminate the tumor.
The researchers noted sustained anti-tumor immunity following treatment. “The immune system built a memory response to the tumor. Once it eradicated tumors, following the initial combination treatment, the mice were shielded against tumor recurrences,” lead author Anthony Park of City of Hope said.
Leishmania vaccine candidate provides immunity in a preclinical study
An attenuated vaccine against Leishmania major protected mice and the disease vector sand flies from infection.Citation7 The parasite causes the tropical disease leishmaniasis with skin lesions in ~2 million people annually. The vaccine is a CRISPR-edited strain with deletion for the centrin gene, which supports the cell structure. “The parasites are unable to proliferate, so they die. But they persist in the body for eight or nine months, which is long enough to generate acquired immunity,” senior author Abhay Satoskar of Ohio State University said.
Vaccinated mice developed no skin lesions, and the vaccine was safe even in immunocompromised animals. Clinical trials are planned to start by 2022.
References
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- Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, Kalofonos H, Radulović S, Demey W, Ullén A, Loriot Y, Sridhar SS, Tsuchiya N, Kopyltsov E, Sternberg CN, Bellmunt J, Aragon-Ching JB, Petrylak DP, Laliberte R, Wang J, Huang B, Davis C, Fowst C, Costa N, Blake-Haskins JA, di Pietro A, Grivas P. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med 2020; 383(13):1218–1230
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- de Streel G, Bertrand C, Chalon N, Liénart S, Bricard O, Lecomte S, Devreux J, Gaignage M, De Boeck G, Mariën L, Van De Walle I, van der Woning B, Saunders M, de Haard H, Vermeersch E, Maes W, Deckmyn H, Coulie PG, van Baren N, Lucas S. Selective inhibition of TGF-β1 produced by GARP-expressing Tregs overcomes resistance to PD-1/PD-L1 blockade in cancer. Nat Commun 2020; 11(1):4545
- Park AK, Fong Y, Kim SI, Yang J, Murad JP, Lu J, Jeang B, Chang WC, Chen NG, Thomas SH, Forman SJ, Priceman SJ. Effective combination immunotherapy using oncolytic viruses to deliver CAR targets to solid tumors. Sci Transl Med 2020; 12(559):eaaz1863
- Zhang WW, Karmakar S, Gannavaram S, Dey R, Lypaczewski P, Ismail N, Siddiqui A, Simonyan V, Oliveira F, Coutinho-Abreu IV, DeSouza-Vieira T, Meneses C, Oristian J, Serafim TD, Musa A, Nakamura R, Saljoughian N, Volpedo G, Satoskar M, Satoskar S, Dagur PK, McCoy JP, Kamhawi S, Valenzuela JG, Hamano S, Satoskar AR, Matlashewski G, Nakhasi HL. A second generation leishmanization vaccine with a markerless attenuated Leishmania major strain using CRISPR gene editing. Nat Commun 2020; 11(1):3461