The Covid-19 pandemics slowly recedes thanks to vaccination
Around 30 million daily vaccine doses are administered globally. China, which accounts for up to 60% of that number, aims to produce three billion doses in 2021 and five billion annual doses in the following years.
In contrast, vaccine rollout in developing countries is lagging behind. Only ~50 million doses have been administered in all of Africa, compared to ~1 billion in China. The G7 countries have therefore pledged almost 900 million doses to the COVAX initiative, which aims to distribute Covid-19 vaccines more equitably throughout the world.
Two inactivated virus vaccines, which account for the majority of doses used in China, namely BIBP (Sinopharm) and CoronaVac (Sinovac), have been approved by the World Health Organization (WHO) for emergency use. They have been shown in clinical trials to prevent 80% and 50–80% of Covid-19 cases, respectively.
Meanwhile, more evidence supports the effectiveness of existing vaccines against emerging variants. Two doses of BNT162b2 (Pfizer & BioNTech) and ChAdOx1-S (AstraZeneca) prevent 96% and 92% hospitalizations due to the Delta variant (B.1.617.2 first identified in India), respectively.Citation1 According to the trial, which involved 14,000 people in UK infected with this strain, no deaths due to Covid-19 occurred in the vaccinated population.
Several countries allow a mixed regimen with the first dose of ChAdOx1-S and the second dose of BNT162b2. Three trials confirm that this approach is comparable in safety and immunogenicity to two doses of BNT162b2.Citation2–4 The mixed regimen might be an option for people who received their first ChAdOx1-S dose in countries that stopped recommending this vaccine due to rare blood clots.
The investigational nanoparticle vaccine NVX-CoV2373 (Novavax) demonstrated 90% and 100% efficacy against symptomatic and severe disease, respectively, in the placebo-controlled Phase 3 PREVENT-19 trial involving 30,000 adults. The vaccine, which is adjuvanted with the Matrix-M system, was highly effective in preventing infection with the Alpha variant (B.1.1.7) in a separate study with 15,000 subjects in UK.
Immunotherapy combination shows promising results in advanced melanoma
The telomerase vaccine UV1 (Ultimovacs) along with the PD-1 inhibitor pembrolizumab (Keytruda, Merck) induced complete responses in 30% of 20 patients with advanced melanoma enrolled in a Phase 1 trial. An additional 30% reported partial responses after a minimum of 18 months. The median progression-free survival was 19 months for the combination compared to a historical 5–12 months for pembrolizumab alone. The treatment was well tolerated without serious adverse events.
UV1, an off-the-shelf peptide vaccine targeting the nearly universal cancer marker telomerase, is designed to induce cellular immunity. It is being tested in various combinations and indications.
Two therapeutic HPV vaccines reduce tumor burden in clinical trials
Ten out of 18 patients with various HPV16-positive cancers, who had failed prior treatment, reported >30% tumor reduction after receiving the nanoparticle lipid vaccine PDS0101 (PDS Biotech). 16 (90%) were alive after 8 months (historical mean survival is 3–11 months). The Phase 2 trial assesses PDS0101 in combination with bintrafusp-alfa (Merck), a drug targeting TGF-β and PD-L1, and IL-12.
Another HPV16-targeting vaccine, HB-200 (Hookipa), was safe and elicited strong CD8+ T cell responses in 38 subjects with metastatic HPV16-positive cancers. Half of evaluable patients had target lesion reduction. HB-200 consists of the E7E6 fusion protein from HPV16 carried by an arenavirus vector.
20-valent pneumococcal vaccine approved in US
The US Food and Drug Administration has approved the 20-valent pneumococcal conjugate vaccine Prevnar 20 (Pfizer) for adults. The vaccine proved safe and immunogenic in a Phase 3 trial with 900 vaccine-naïve people.
Prevnar 20 targets the 13 strains included in its predecessor Prevnar 13 and seven additional strains associated with antibiotic resistance and invasive disease with high fatality rates. The vaccine consists of capsule polysaccharides from Streptococcus pneumoniae each conjugated to a diphtheria toxoid.
Neoantigen vaccine demonstrate long-term immunogenicity in solid tumors
The neoantigen vaccine GEN-009 (Genocea) in combination with a PD-1 inhibitor showed long-term antitumor activity in patients with advanced or metastatic solid tumors. Four of nine subjects who responded to checkpoint inhibition, the median progression-free survival was 15 months following GEN-009 vaccination. Two of seven patients refractory to checkpoint inhibition had stable disease for 10 months.
In the GEN-009 approach the patient’s tumor is sequenced for in silico identification of potentially immunogenic neoantigens, which are then expressed in autologous dendritic cells for ex vivo stimulation of the subject’s own T cells.
Allogeneic CAR-T cell therapy was beneficial for non-Hodgkin lymphoma patients
30% of subjects with large B-cell lymphoma and follicular lymphoma reported complete responses six months following treatment with the allogeneic CAR-T cell therapy ALLO-501 (Allogene Therapeutics). The Phase 1 ALLO-501 ALPHA trial, which enrolled 32 patients with no history of autologous CAR-T therapy, saw no dose-limiting toxicities or graft-versus-host disease.
The ALLO-501 immunotherapy, which targets the B-cell receptor CD19, contrasts approved CAR-T cell protocols in that the infused cells are not patients’ own and can be stockpiled and used as an off-the-shelf treatment.
Immune-stimulating therapy active against NSCLC and other solid tumors
The dendritic cell activator eftilagimod alpha (efti, Immutep) in combination with pembrolizumab induced responses in 15 of 36 patients with non-small cell lung cancer as the first-line treatment in the Phase 2 TACTI-002 trial. Ten additional subjects had disease stabilization. The numbers were 11 and 3, respectively, in 37 patients with squamous cell carcinoma of the head and neck, who received efti as the second-line therapy.
In the Phase 1 INSIGHT-004 trial, efti was tested with the PD-L1 inhibitor avelumab (Bavencio, Merck) in 12 people with various solid tumors. The treatment was well tolerated and was able to stabilize disease in half of the participants with five partial responses.
Efti, which is a soluble form of the dendritic-cell activator LAG-3 fused to the IgG Fc region, is designed to induce antigen presentation and antitumor CD8+ T-cell responses.
Cellular immunotherapy active against lymphoma in an early trial
Eight of 11 patients with relapsed B-cell lymphoma responded to the natural killer (NK) cell immunotherapy FT516 (Fate Therapeutics), with six complete responses. According to interim data from a dose-escalation Phase 1 trial, the treatment was safe with no serious adverse events.
FT516 consists of NKs derived from an induced pluripotent stem cell line with engineered high-affinity, non-cleavable CD16 Fc receptor. When administered together with the CD20-specific rituximab (Rituxan, Genentech), the NK cells are targeted to the CD20-expressing tumor, which results in antibody-dependent cellular toxicity killing of the cancer cells.
New checkpoint inhibitor benefits nasopharyngeal carcinoma patients
The PD-1 inhibitor toripalimab (Junshi Biosciences) in combination with chemotherapy improved progression-free survival and duration of response compared to chemotherapy alone in subjects with recurrent or metastatic nasopharyngeal carcinoma. The randomized, double-blind, placebo-controlled Phase 3 JUPITER-02 trial tested the combination as the first-line treatment in almost 300 patients.
The interim analysis reported 12 vs. 8 months of progression-free survival and objective response rates of 77% vs. 66% in the experimental and control groups, respectively. There was a 40% reduction in mortality at the time of analysis. The clinical benefits were observed in all participants irrespective of their PD-L1 levels.
Ebola vaccine regimen endorsed by WHO
The WHO’s Strategic Advisory Group of Experts on Immunization recommended the Ebola vaccines Ad26.ZEBOV (J&J) and MVA-BN-Filo (Bavarian Nordic) for use during outbreaks in individuals at high risk of exposure, and outside of outbreak settings in international humanitarian responders. The vaccines, which are administered as a heterologous prime-boost regimen, follow rVSV-ZEBOV (Merck) prequalified in 2019 and used widely during the most recent epidemic in West Africa.
Disclosure statement
No potential conflicts of interest were disclosed.
References
- Stowe J, Andrews N, Gower C, Gallagher E, Utsi L, Simmons R, Thelwall S, Tessier E, Groves N, Dabrera G, et al. Effectiveness of COVID-19 vaccines against hospital admission with the Delta (B.1.617.2) variant. KnowledgeHub [Preprint]. 2021 June 17. accessed https://khub.net/documents/135939561/479607266/Effectiveness+of+COVID-19+vaccines+against+hospital+admission+with+the+Delta+%28B.1.617.2%29+variant.pdf/1c213463-3997-ed16-2a6f-14e5deb0b997
- Borobia AM, Carcas AJ, Pérez Olmeda MT, Castaño L, Jesús Bertrán M, García-Pérez J, Campins M, Portolés A, Gonzalez-Perez M, García Morales MT, et al., CombiVacS Study Group. Reactogenicity and Immunogenicity of BNT162b2 in subjects having received a first dose of ChAdOx1s: initial results of a randomised, adaptive, phase 2 trial (CombiVacS). SSRN [Preprint]. 2021. https://ssrn.com/abstract=3854768
- Hillus D, Schwarz T, Tober-Lau P, Hastor H, Thibeault C, Kasper S, Helbig ET, Lippert LJ, Tscheak P, Schmidt ML, et al., Safety, reactogenicity, and immunogenicity of homologous and heterologous prime-boost immunisation with ChAdOx1-nCoV19 and BNT162b2: a prospective cohort study. MedRxiv [Preprint]. 2021. doi:10.1101/2021.05.19.21257334.
- Groß R, Zanoni M, Seidel A, Conzelmann C, Gilg A, Krnavek D, Erdemci-Evin S, Mayer B, Hoffmann M, Pöhlmann S, et al. Heterologous ChAdOx1 nCoV-19 and BNT162b2 prime-boost vaccination elicits potent neutralizing antibody responses and T cell reactivity. MedRxiv [Preprint]. 2021. doi:10.1101/2021.05.30.21257971.