Unlocking cancer vaccine potential: What are the key factors?

Cancer is a global health challenge, with changing demographics and lifestyle factors producing an increasing burden worldwide. Screening advancements are enabling earlier diagnoses, but current cancer immunotherapies only induce remission in a small proportion of patients and come at a high cost. Cancer vaccines may offer a solution to these challenges, but they have been mired by poor results in past decades. Greater understanding of tumor biology, coupled with the success of vaccine technologies during the COVID-19 pandemic, has reinvigorated cancer vaccine development. With the first signs of efficacy being reported, cancer vaccines may be beginning to fulfill their potential. Solid tumors, however, present different hurdles than infectious diseases. Combining insights from previous cancer vaccine clinical development and contemporary knowledge of tumor immunology, we ask: who are the 'right' patients, what are the 'right' targets, and which are the 'right' modalities to maximize the chances of cancer vaccine success?

An Encodable Scaffold for Sequence-Specific Recognition of Duplex RNA.

RNA, unlike DNA, folds into a multitude of secondary and tertiary structures. This structural diversity has impeded the development of ligands that can sequence-specifically target this biomolecule. We sought to develop ligands for double-stranded RNA (dsRNA) segments, which are ubiquitous in RNA tertiary structure. The major groove of double-stranded DNA is sequence-specifically recognized by a range of dimeric helical transcription factors, including the basic leucine zippers (bZIP) and basic helix-loop-helix (bHLH) proteins; however, such simple structural motifs are not prevalent in RNA-binding proteins. We interrogated the high-resolution structures of DNA and RNA to identify requirements for a helix fork motif to occupy dsRNA major grooves akin to dsDNA. Our analysis suggested that the rigidity and angle of approach of dimeric helices in bZIP/bHLH motifs are not ideal for the binding of dsRNA major grooves. This investigation revealed that the replacement of the leucine zipper motifs in bHLH proteins with synthetic crosslinkers would allow recognition of dsRNA. We show that a model bHLH DNA-binding motif does not bind dsRNA but can be reengineered as an RNA ligand. Based on this hypothesis, we rationally designed a miniature synthetic crosslinked helix fork (CHF) as a generalizable proteomimetic scaffold for targeting dsRNA. We evaluated several CHF constructs against a set of RNA and DNA hairpins to probe the specificity of the designed construct. Our studies reveal a new class of proteomimetics as an encodable platform for sequence-specific recognition of dsRNA.

Persistence of immunogenicity after seven COVID-19 vaccines given as third dose boosters following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK: Three month analyses of the COV-BOOST trial.

OBJECTIVES: To evaluate the persistence of immunogenicity three months after third dose boosters. METHODS: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of seven COVID-19 vaccines used as a third booster dose. The analysis was conducted using all randomised participants who were SARS-CoV-2 naïve during the study. RESULTS: Amongst the 2883 participants randomised, there were 2422 SARS-CoV-2 naïve participants until D84 visit included in the analysis with median age of 70 (IQR: 30-94) years. In the participants who had two initial doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd), schedules using mRNA vaccines as third dose have the highest anti-spike IgG at D84 (e.g. geometric mean concentration of 8674 ELU/ml (95% CI: 7461-10,085) following ChAd/ChAd/BNT162b2 (Pfizer-BioNtech, hearafter referred to as BNT)). However, in people who had two initial doses of BNT there was no significant difference at D84 in people given ChAd versus BNT (geometric mean ratio (GMR) of 0.95 (95%CI: 0.78, 1.15). Also, people given Ad26.COV2.S (Janssen; hereafter referred to as Ad26) as a third dose had significantly higher anti-spike IgG at D84 than BNT (GMR of 1.20, 95%CI: 1.01,1.43). Responses at D84 between people who received BNT (15 µg) or BNT (30 µg) after ChAd/ChAd or BNT/BNT were similar, with anti-spike IgG GMRs of half-BNT (15 µg) versus BNT (30 µg) ranging between 0.74-0.86. The decay rate of cellular responses were similar between all the vaccine schedules and doses. CONCLUSIONS: 84 days after a third dose of COVID-19 vaccine the decay rates of humoral response were different between vaccines. Adenoviral vector vaccine anti-spike IgG concentrations at D84 following BNT/BNT initial doses were similar to or even higher than for a three dose (BNT/BNT/BNT) schedule. Half dose BNT immune responses were similar to full dose responses. While high antibody tires are desirable in situations of high transmission of new variants of concern, the maintenance of immune responses that confer long-lasting protection against severe disease or death is also of critical importance. Policymakers may also consider adenoviral vector, fractional dose of mRNA, or other non-mRNA vaccines as third doses.

Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial.

BACKGROUND: Few data exist on the comparative safety and immunogenicity of different COVID-19 vaccines given as a third (booster) dose. To generate data to optimise selection of booster vaccines, we investigated the reactogenicity and immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer-BioNtech, hearafter referred to as BNT). METHODS: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of third dose booster vaccination against COVID-19. Participants were aged older than 30 years, and were at least 70 days post two doses of ChAd or at least 84 days post two doses of BNT primary COVID-19 immunisation course, with no history of laboratory-confirmed SARS-CoV-2 infection. 18 sites were split into three groups (A, B, and C). Within each site group (A, B, or C), participants were randomly assigned to an experimental vaccine or control. Group A received NVX-CoV2373 (Novavax; hereafter referred to as NVX), a half dose of NVX, ChAd, or quadrivalent meningococcal conjugate vaccine (MenACWY)control (1:1:1:1). Group B received BNT, VLA2001 (Valneva; hereafter referred to as VLA), a half dose of VLA, Ad26.COV2.S (Janssen; hereafter referred to as Ad26) or MenACWY (1:1:1:1:1). Group C received mRNA1273 (Moderna; hereafter referred to as m1273), CVnCov (CureVac; hereafter referred to as CVn), a half dose of BNT, or MenACWY (1:1:1:1). Participants and all investigatory staff were blinded to treatment allocation. Coprimary outcomes were safety and reactogenicity and immunogenicity of anti-spike IgG measured by ELISA. The primary analysis for immunogenicity was on a modified intention-to-treat basis; safety and reactogenicity were assessed in the intention-to-treat population. Secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ISRCTN, number 73765130. FINDINGS: Between June 1 and June 30, 2021, 3498 people were screened. 2878 participants met eligibility criteria and received COVID-19 vaccine or control. The median ages of ChAd/ChAd-primed participants were 53 years (IQR 44-61) in the younger age group and 76 years (73-78) in the older age group. In the BNT/BNT-primed participants, the median ages were 51 years (41-59) in the younger age group and 78 years (75-82) in the older age group. In the ChAd/ChAD-primed group, 676 (46·7%) participants were female and 1380 (95·4%) were White, and in the BNT/BNT-primed group 770 (53·6%) participants were female and 1321 (91·9%) were White. Three vaccines showed overall increased reactogenicity: m1273 after ChAd/ChAd or BNT/BNT; and ChAd and Ad26 after BNT/BNT. For ChAd/ChAd-primed individuals, spike IgG geometric mean ratios (GMRs) between study vaccines and controls ranged from 1·8 (99% CI 1·5-2·3) in the half VLA group to 32·3 (24·8-42·0) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·1 (95% CI 0·7-1·6) for ChAd to 3·6 (2·4-5·5) for m1273. For BNT/BNT-primed individuals, spike IgG GMRs ranged from 1·3 (99% CI 1·0-1·5) in the half VLA group to 11·5 (9·4-14·1) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·0 (95% CI 0·7-1·6) for half VLA to 4·7 (3·1-7·1) for m1273. The results were similar between those aged 30-69 years and those aged 70 years and older. Fatigue and pain were the most common solicited local and systemic adverse events, experienced more in people aged 30-69 years than those aged 70 years or older. Serious adverse events were uncommon, similar in active vaccine and control groups. In total, there were 24 serious adverse events: five in the control group (two in control group A, three in control group B, and zero in control group C), two in Ad26, five in VLA, one in VLA-half, one in BNT, two in BNT-half, two in ChAd, one in CVn, two in NVX, two in NVX-half, and one in m1273. INTERPRETATION: All study vaccines boosted antibody and neutralising responses after ChAd/ChAd initial course and all except one after BNT/BNT, with no safety concerns. Substantial differences in humoral and cellular responses, and vaccine availability will influence policy choices for booster vaccination. FUNDING: UK Vaccine Taskforce and National Institute for Health Research.

Posttraumatic growth in aging individuals who have lost their only child in China.

This article examined the extent of posttraumatic growth (PTG) and factors related to PTG in aging individuals who have lost their only child in China. The sample included 201 bereaved parents from different families residing in Chongqing, China. They were between 49-80 years old (M = 61) and had lost their only child. Personal interviews were conducted in their homes. PTG was assessed with a revised Posttraumatic Growth Inventory (PTGI-R). Descriptive and multiple linear regression analyses were conducted. Overall, the sample showed a positive tendency toward PTG. The older the child was at death, the less PTG the parent experienced. Time since the child's death was negatively correlated with PTG, and parents whose children died by accident/suicide had lower PTG than those whose children died of illness. Lower education and poor parental health were significantly associated with lower levels of PTG. Community support was significantly and positively associated with PTG. A majority of aging parents who have lost their only child in China experience PTG. Characteristics related to the loss (child's age at death, time since the death, and cause of death), personal resources (parent's education and health), and community support are associated with the degree of growth.

Analysis of interaction of acute atrial overdrive pacing with sleep-related breathing disorder.

Dose-related effects of atrial overdrive pacing (AOP) on sleep-related breathing disorder (SRBD) were studied. Fourteen patients with pacemakers with moderate to severe SRBD (mean screening apnea-hypopnea index [AHI] 35.2 +/- 21.9 events/hour) were randomized to 3 levels of pacing (50, 10, and 20 beats/min greater than the mean nocturnal heart rate) and studied by polysomnography, observing for changes in AHI. At the 2 AOP levels, no significant change was observed in the primary end point of reduction in AHI. Additionally, there was no observed impact on secondary end points of the study. Cyclic variation of heart rate was progressively abolished with higher levels of AOP without affecting AHI. Large variations were observed between the screening and control studies in SRBD indexes in a number of patients. In conclusion, AOP demonstrated no benefit to predominantly obstructive SRBD disorder of at least moderate severity.

Feasibility of automated detection of advanced sleep disordered breathing utilizing an implantable pacemaker ventilation sensor.

OBJECTIVES: This study tested the feasibility of automatically detecting advanced sleep disordered breathing (SDB) from a pacemaker trans-thoracic impedance sensor. BACKGROUND: SDB is prevalent yet under-diagnosed in patients with cardiovascular disease. The potential for automated detection of SDB in patients receiving pacemakers with respiration sensors has not been fully explored. We hypothesized that the trans-thoracic impedance sensor could be utilized for automatic detection of advanced SDB. METHODS: Patients underwent overnight polysomnography (PSG). The pacemaker trans-thoracic impedance signal was simultaneously recorded and time synchronized with the polysomnograph. Cardiovascular health variables were abstracted from medical records. Apnea was defined as cessation of inspiratory airflow lasting 10 seconds or longer. Hypopnea was defined as a reduction of tidal volume of at least 30% from baseline tidal volume, lasting 10 seconds or more. A computer algorithm (PM-A) was developed to automatically detect SDB from the pacemaker impedance sensor data. The performance of automated SDB detection was compared against PSG. RESULTS: Sixty patients (aged 69 +/- 12 years, 45 males) were studied. Advanced SDB (moderate or severe) was diagnosed in 40 patients. Severe SDB (apnea-hypopnea index [AHI]> or = 30) was diagnosed in 32 patients (53%), but only 5 patients had prior diagnosis of the disease. Moderate SDB (30 > AHI > 15) was diagnosed in 8 patients of whom only two were previously diagnosed. Cardiovascular health variables did not predict the presence of advanced SDB. PM-A derived AHI correlated with that of the PSG (r = 0.80, P < 0.01). The algorithm identified patients with advanced SDB with 82% sensitivity and 88% specificity. CONCLUSIONS: It is feasible to automatically measure SDB severity using a pacemaker trans-thoracic impedance sensor. Advanced SDB was frequently undiagnosed in this cohort of pacemaker patients.