A quantitative evaluation of the impact of vaccine roll-out rate and coverage on reducing deaths from COVID-19: a counterfactual study on the impact of the delayed vaccination programme in Iran (preprint)

Vaccination has been a crucial factor in the fight against COVID-19 because of its effectiveness in suppressing virus circulation, lowering the risk of severe disease, and ultimately saving lives. Many countries with an early and rapid distribution of COVID-19 vaccines performed much better in reducing their total number of deaths than those with lower coverage and slower roll-out pace. However, we still do not know how many more deaths could have been averted if countries with slower vaccine roll-outs followed the same rate as countries with earlier and faster distribution of vaccines. Here, we investigated counterfactual scenarios for the number of avertable COVID-19 deaths in a given country based on other countries vaccine roll-out rates. As a case study, we compared Iran to eight model countries with similar income brackets and dominant COVID-19 vaccine types. Our analysis revealed that faster roll-outs were associated with higher numbers of averted deaths. While Irans percentage of fully vaccinated individuals would have been similar to Bangladesh, Nepal, Sri Lanka, and Turkey under counterfactual roll-out rates, adopting Turkeys rates could have averted up to 50,000 more deaths, whereas following Bangladeshs rates could have led to up to 52,800 additional losses of lives in Iran. Notably, a counterfactual scenario based on Argentinas early but slow roll-out rate resulted in a smaller number of averted deaths in Iran, up to 12,600 more individuals. Following Montenegros or Bolivias model of faster per capita roll-out rates for Iran could have resulted in more averted deaths in older age groups, particularly during the Alpha and Delta waves, despite their lower overall coverage. Also, following Bahrains model as an upper bound benchmark, Iran could have averted 75,300 deaths throughout the pandemic, primarily in the >50 age groups. This study provides insights into future decisions on the management of infectious disease epidemics through vaccination strategies by comparing the relative performance of different countries in terms of their timing, pace, and coverage of vaccination in preventing COVID-19 deaths.

Single dose of BNT162b2 mRNA vaccine against SARS-CoV-2 induces high frequency of neutralising antibody and polyfunctional T-cell responses in patients with myeloproliferative neoplasms (preprint)

Encouraging results have been observed from initial studies evaluating vaccines targeting the novel beta coronavirus which causes severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, concerns have been raised around the efficacy of these vaccines in immunosuppressed populations, including patients with haematological malignancy. Myeloproliferative neoplasms (MPN), in particular myelofibrosis (MF), are associated with heterogenous immune defects which are influenced by patient age, disease subtype and the use of cytoreductive therapies. Patients with a WHO defined diagnosis of an MPN presenting to our clinic were recruited following first injection of 30μg BNT162b2. A positive anti-S IgG ELISA was seen in 76.1% (16) of patients following vaccination with positive neutralising antibodies detected in 85.7% (18) of patients. A memory T cell response was observed in 80% (16) of patients, with a CD4+ T cell response in 75% (15) and a CD8+ T cell response in 35% (7). These results, for the first time, provide some reassurance regarding the initial immune response to the BNT162b2 vaccine amongst patients with MPN, with response rates similar to that observed in the general population.

Single dose of BNT162b2 mRNA vaccine against SARS-CoV2 induces neutralizing antibody and polyfunctional T-cell responses in patients with CML (preprint)

Patients receiving targeted cancer treatments such as tyrosine kinase inhibitors (TKIs) have been classified in the clinically extremely vulnerable group to develop severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including patients with Chronic Myeloid Leukaemia (CML) taking TKIs. In addition, concerns that immunocompromised individuals with solid and haematological malignancies may not mount an adequate immune response to a single dose of SARS-CoV-2 BNT162b2 (Pfizer- BioNTech) vaccine have been raised. We evaluated humoral and cellular immune responses after a first injection of BNT162b2 vaccine in 16 CML patients. Seroconversion and cellular immune response prior and after vaccination were assessed. By day 21 post-vaccination, anti-Spike IgG were detected in 14/16 (87.5%) of CML patients and all developed a neutralizing antibody response (ID50>50), including medium (ID50 of 200-500) or high (501-2000) neutralising antibodies titres in 9/16 (56.25%) patients. T cell response was seen in 14/15 (93.3%) evaluable patients, with polyfunctional responses seen in 12/15 (80%) patients (polyfunctional CD4+ response 9/15, polyfunctional CD8+ T cell response 9/15). These data demonstrate the immunogenicity of a single dose of SARS-CoV-2 BNT162b2 vaccine in most CML patients with both neutralizing antibodies and polyfunctional T-cell responses seen, in contrast to patients with solid tumour or lymphoid haematological malignancies.

SARS-CoV2 drives JAK1/2-dependent local and systemic complement hyper-activation (preprint)

Patients with coronavirus disease 2019 (COVID-19) present with a range of devastating acute clinical manifestations affecting the lungs, liver, kidneys and gut. The best-characterized entry receptor for the disease-causing virus SARS-CoV2, angiotensin converting enzyme (ACE) 2, is highly expressed in these tissues. However, the pathways that underlie the disease are still poorly understood. Here we show that the complement system is unexpectedly one of the intracellular pathways most highly induced by SARS-CoV2 infection in lung epithelial and liver cells. Within cells of the bronchoalveolar lavage of patients, distinct signatures of complement activation in myeloid, lymphoid and epithelial cells tracked with disease severity. Modelling the regulome of host genes induced by COVID-19 and the drugs that could normalize these genes both implicated the JAK1/2-STAT1 signaling system downstream of type I interferon receptors, and NF-kB. Ruxolitinib, a JAK1/2 inhibitor and the top predicted pharmaceutical candidate, normalized interferon signature genes, IL-6 (the best characterized severity marker in COVID-19) and all complement genes induced by SARS-CoV2, but did not affect NF-kB-regulated genes. We predict that combination therapy with JAK inhibitors and other agents with the potential to normalize NF-kB-signaling, such as anti-viral agents, may serve as an effective clinical strategy. 

Factors affecting COVID-19 outcomes in cancer patients - A first report from Guys Cancer Centre in London (preprint)

BackgroundThere is insufficient evidence to support clinical decision-making for cancer patients diagnosed with COVID-19 due to the lack of large studies. MethodsWe used data from a single large UK Cancer Centre to assess demographic/clinical characteristics of 156 cancer patients with a confirmed COVID-19 diagnosis between 29 February-12 May 2020. Logistic/Cox proportional hazards models were used to identify which demographic and/or clinical characteristics were associated with COVID-19 severity/death. Results128 (82%) presented with mild/moderate COVID-19 and 28 (18%) with severe disease. Initial diagnosis of cancer >24m before COVID-19 (OR:1.74 (95%CI: 0.71-4.26)), presenting with fever (6.21 (1.76-21.99)), dyspnoea (2.60 (1.00-6.76)), gastro-intestinal symptoms (7.38 (2.71-20.16)), or higher levels of CRP (9.43 (0.73-121.12)) were linked with greater COVID-19 severity. During median follow-up of 47d, 34 patients had died of COVID-19 (22%). Asian ethnicity (3.73 (1.28-10.91), palliative treatment (5.74 (1.15-28.79), initial diagnosis of cancer >24m before (2.14 (1.04-4.44), dyspnoea (4.94 (1.99-12.25), and increased CRP levels (10.35 (1.0552.21)) were positively associated with COVID-19 death. An inverse association was observed with increased levels of albumin (0.04 (0.01-0.04). ConclusionsA longer-established diagnosis of cancer was associated with increasing severity of infection as well as COVID-19 death, possibly reflecting effects of more advanced malignant disease impact on this infection. Asian ethnicity and palliative treatment were also associated with COVID-19 death in cancer patients. Contribution to the fieldIn the context of cancer, the COVID-19 pandemic has led to challenging decision-making. These are supported by limited evidence with small case studies being reported from China, Italy, New York and a recent consortium of 900 patients from over 85 hospitals in the USA, Canada, and Spain. As a result of their limited sample sizes, most studies were not able to distinguish between the effects of age, cancer, and other comorbidities on COVID-19 outcomes. Moreover, the case series from New York analysed which patient characteristics are associated with COVID-19 death, but only made a comparison with non-cancer patients. The first results of the COVID-19 and Cancer Consortium provide insights from a large cohort in terms of COVID-19 mortality, though a wide variety of institutions with different COVID-19 testing procedures were included. Given the current lack of (inter)national guidance for cancer patients in the context of COVID-19, we believe that our large cancer centre can provide an important contribution to the urgent need for further insight into the intersection between COVID-19 and cancer. With comprehensive in-house patient details, consistent inclusion criteria and up-to-date cancer and COVID-19 outcomes, we are in position to provide rapid analytical information to the oncological community.