As mass vaccination against Covid-19 progresses throughout the world, attention is increasingly focused on emerging variants of the virus. The hyper-transmissible lineage P.1 first isolated in travelers from Brazil can reinfect some people who recovered from previous infection with the parental strain. It is less susceptible to neutralization by antibodies elicited by both natural infection and vaccination.Citation1
The most widely used vaccine BNT162b2 (Pfizer and BioNTech) is being adapted in development to new variants by changing the mRNA sequence in the lipid nanoparticle. Regulators are discussing ways to facilitate review of these new variant vaccines. A clinical trial has started that evaluates a third, booster dose of BNT162b2 6–12 months after the initial two-dose regimen for protection against emerging strains. A similar approach is planned for the mRNA-1273 vaccine (Moderna).
Initial preclinical data suggest that another mRNA vaccine CVnCoV (CureVac) is effective against two hyper-transmissible strains isolated in the UK and South Africa. CVnCoV, which is being evaluated in late-stage trials, started a rolling review process with the European Medicines Agency (EMA).
Big pharma companies are collaborating in an unprecedented way to increase the production of approved vaccines. Merck will also produce J&J’s single-dose non-replicating adenovirus-based vaccine Ad26.COV2.S, which was recently approved in the US and Canada. Novartis has entered agreements with Pfizer/BioNTech and CureVac to also produce their respective vaccines. Polish Mabion will manufacture Novavax’ nanoparticle protein vaccine NVX-CoV2373.
Further clinical trials are underway. A study monitoring British health-care workers found that a single dose of BNT162b2 prevented 75% of asymptomatic infections, which implies that the vaccine has major potential for preventing transmission.Citation2 A small study also suggested that vaccine-induced antibodies pass into the milk of breastfeeding mothers vaccinated with BNT162b2.Citation3
A whole-virion inactivated vaccine Covaxin (Ocugen & Bharat Biotech) was 80% effective in preventing Covid-19, according to preliminary data of a placebo-controlled Phase 3 trial involving 26,000 adults in India. Symptomatic disease appeared in 7 and 36 individuals in the equally large experimental and placebo groups, respectively.
A Phase 1 trial is testing the single-dose intranasal adenovirus-based AdCOVID vaccine (Altimmune) in 180 healthy adults. The capsid virus-like particle vaccine ABNCoV2 (AdaptVac and Bavarian Nordic), which showed strong immunogenicity and protective efficacy in animal studies, is being tested with or without adjuvant in a Phase 1/2 dose-escalation trial in 40 healthy adults.
China has approved two more domestic vaccines, raising the number of vaccines deployed in the country to four: two developed by Sinopharm using similar technologies (70% and 80% efficacies in clinical trials), one by Sinovac (50% effective), and one by CanSino (70% effective).
Immunotherapy delays onset of type 1 diabetes
The anti-CD3 MAb teplizumab (PRV-031, Provention Bio) delayed onset of type 1 diabetes (T1D) and insulin dependence by almost three years.Citation4 In a Phase 2 TN-10 trial, median time to clinical disease was 5 years in subjects who received a single 14-day infusion of teplizumab, compared to 2 years in the placebo group. All participants had preexisting diabetes-related autoantibodies and dysglycemia, and thus were at high risk of developing T1D.
Teplizumab, which targets the T-cell surface receptor CD3, is under priority review by both the US Food and Drug Administration (FDA) and EMA for delay or prevention of T1D. It has been shown in earlier studies to preserve beta-cell function and insulin production.
Oncolytic virotherapy fast-tracked by FDA
The FDA has granted the Fast-Track designation to the oncolytic immunotherapeutic virus ONCOS-102 (Targovax) for treatment of malignant pleural mesothelioma. The decision is based on clinical data indicating that ONCOS-102 induces broad immune responses targeted against the tumor.
ONCOS-102 is based on adenoviral type 3 and 5 chimeric capsid carrying the immunostimulant GM-CSF. It was shown to be well tolerated and to induce CD8+ tumor-infiltrating lymphocytes. ONCOS-102 can also be used to sensitize the tumor microenvironment to treatment with checkpoint blockade immunotherapy.
Lyme disease vaccine starts a phase 2 trial
A randomized, observer-blind, placebo-controlled Phase 2 VLA15-221 trial has commenced to investigate safety and immunogenicity of the Lyme disease vaccine candidate VLA-15 (Valneva) in subjects aged 5–65 years. Six hundred participants will be randomized to receive two (0–6 months) or three (0-2-6 months) doses of VLA15 or placebo, and a subset will receive a third dose at Month 18.
VLA15 is an aluminum-adjuvanted hexavalent subunit vaccine targeting the outer membrane protein OspA from the causative agent of Lyme disease, the bacterium Borrelia burgdorferi.
Safety switch can alleviate serious adverse events of CAR-T cell therapy, case study suggests
CAR-T cell therapy can be improved with a safety switch to prevent serious adverse events.Citation5 The CAR-T cell approach, in which patients’ own T cells are engineered to target B-cell-specific CD19 tumor marker, has been approved for treatment of several types of blood cancer, but life-threatening adverse events are often reported. The switch consists of the recombinant inducible caspase-9, which triggers apoptosis in the presence of the drug rimiducid. It is being tested in patients with relapsed or refractory B-cell acute lymphoblastic leukemia. One participant, a 26-year-old woman, experienced severe immune effector cell-associated neurotoxicity syndrome. Following rimiducid administration, the severity was reduced and the number of circulating CAR-T cells decreased by 90% within 24 hours.
“It should be noted that while rimiducid mitigated her toxicities, it also lowered the number of […] T cells fighting her cancer by 90%. But there seemed to be sufficient T-cells still circulating to maintain an anticancer response,” senior author Gianpietro Dotti of University of North Carolina said.
Bispecific antibodies show promising antitumor activity in preclinical models
Antibodies targeting simultaneously a cancer neoantigen and a T-cell antigen might facilitate tumor killing by the immune system. By bringing T cells in close proximity to the tumor, scientists were able to slow malignant growth in a cell culture or in mice in three different hard-to-treat cancers: T-cell leukemiaCitation6 and tumors with p53 and RAS mutations.Citation7,Citation8
References
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- Sims EK, Bundy BN, Stier K, Serti E, Lim N, Long SA, Geyer SM, Moran A, Greenbaum CJ, Evans-Molina C, et al., Type 1 Diabetes TrialNet Study Group. Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals. Sci Transl Med. 2021;13(583):eabc8980. doi:10.1126/scitranslmed.abc8980.
- Foster MC, Savoldo B, Lau W, Rubinos CA, Grover N, Armistead PM, Coghill JM, Hagan RS, Morrison JK, Cheng C, et al. Utility of safety switch to abrogate CD19.CAR T cell-associated neurotoxicity. Blood. 2021. doi:10.1182/blood.2021010784.
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