Measuring vaccine efficacy against infection and disease in clinical trials: sources and magnitude of bias in COVID-19 vaccine efficacy estimates

Background Phase III trials have estimated COVID-19 vaccine efficacy (VE) against symptomatic and asymptomatic infection. We explore the direction and magnitude of potential biases in these estimates and their implications for vaccine protection against infection and against disease in breakthrough infections. Methods We developed a mathematical model that accounts for natural and vaccine-induced immunity, changes in serostatus and imperfect sensitivity and specificity of tests for infection and antibodies. We estimated expected biases in VE against symptomatic, asymptomatic and any SARS-CoV-2 infections and against disease following infection for a range of vaccine characteristics and measurement approaches, and the likely overall biases for published trial results that included asymptomatic infections. Results VE against asymptomatic infection measured by PCR or serology is expected to be low or negative for vaccines that prevent disease but not infection. VE against any infection is overestimated when asymptomatic infections are less likely to be detected than symptomatic infections and the vaccine protects against symptom development. A competing bias towards underestimation arises for estimates based on tests with imperfect specificity, especially when testing is performed frequently. Our model indicates considerable uncertainty in Oxford-AstraZeneca ChAdOx1 and Janssen Ad26.COV2.S VE against any infection, with slightly higher than published, bias-adjusted values of 59.0% (95% uncertainty interval [UI] 38.4 to 77.1) and 70.9% (95% UI 49.8 to 80.7) respectively. Conclusion Multiple biases are likely to influence COVID-19 VE estimates, potentially explaining the observed difference between ChAdOx1 and Ad26.COV2.S vaccines. These biases should be considered when interpreting both efficacy and effectiveness study results.

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Killing of Borrelia burgdorferi by Antibody Elicited by OspA Vaccine Is Inefficient in the Absence of Complement

Infection and Immunity ◽

10.1128/iai.67.1.443-445.1999 ◽

1999 ◽

Vol 67 (1) ◽

pp. 443-445 ◽

Cited By ~ 20

Author(s):

Jena M. Nowling ◽

Mario T. Philipp

Keyword(s):

Borrelia Burgdorferi ◽

Antibody Titer ◽

Vaccine Efficacy ◽

Rhesus Monkeys ◽

Phase Iii ◽

Tick Saliva ◽

Tick Vector ◽

Lyme Disease Vaccine ◽

Phase Iii Trials

ABSTRACT A Lyme disease vaccine, based on the Borrelia burgdorferi lipoprotein OspA, has recently undergone phase III trials in humans. The results of one of these trials indicate that vaccine efficacy positively correlates with anti-OspA antibody titer. Spirochete killing within the tick vector midgut, upon which vaccine efficacy appears to depend, may occur chiefly via a mechanism that involves antibody alone, as it has been reported that complement is degraded by tick saliva decomplementing factors. We compared the in vitro killing efficiencies of anti-OspA antibody elicited in rhesus monkeys by the OspA vaccine, in the presence and in the absence of monkey complement. Killing in the absence of complement was between 14 and 3,800 times less efficient than with complement present, depending on the spirochete strain. The relative inefficiency of the complement-independent killing mechanism by anti-OspA antibody may explain why OspA vaccine efficacy is critically dependent on antibody titer.

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Efficacy and effectiveness of COVID-19 vaccines against SARS-CoV-2 infection: interim results of a living systematic review, 1 January to 14 May 2021

Eurosurveillance ◽

10.2807/1560-7917.es.2021.26.28.2100563 ◽

2021 ◽

Vol 26 (28) ◽

Author(s):

Thomas Harder ◽

Judith Koch ◽

Sabine Vygen-Bonnet ◽

Wiebe Külper-Schiek ◽

Antonia Pilic ◽

...

Keyword(s):

Public Health ◽

Systematic Review ◽

Vaccine Efficacy ◽

Asymptomatic Infection ◽

Asymptomatic Infections

Evidence on COVID-19 vaccine efficacy/effectiveness (VE) in preventing asymptomatic SARS-CoV-2 infections is needed to guide public health recommendations for vaccinated people. We report interim results of a living systematic review. We identified a total of 30 studies that investigated VE against symptomatic and/or asymptomatic infection. In fully vaccinated individuals, VE against symptomatic and asymptomatic infections was 80–90% in nearly all studies. Fully vaccinated persons are less likely to become infected and contribute to transmission.

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Safety summary of panitumumab (pmab) in combination with chemotherapy (ctx) from four clinical trials in patients (pts) with metastatic colorectal cancer (mCRC)

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e15005 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e15005-e15005

Author(s):

T. J. Price ◽

M. Peeters ◽

J. Douillard ◽

E. Mitchell ◽

A. Cohn ◽

...

Keyword(s):

Phase Ii ◽

Safety Data ◽

Data Monitoring Committee ◽

Phase Iii ◽

Phase Ii Trials ◽

Two Phase ◽

Phase Ii Studies ◽

Study Results ◽

Phase Iii Trials ◽

Phase Iii Studies

e15005 Background: Pmab is a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody approved in the US and EU (wild-type KRAS) as monotherapy for pts with mCRC. Safety data from 4 studies (Siena et al ASCO 2008; Peeters et al ASCO 2008; Cohn et al ASCO 2008; Mitchell et al WORLD GI 2008) of pmab in combination with ctx are summarized. Methods: Two studies are single-arm, phase II trials and two are randomized, phase III trials with pooled, blinded safety data that include ctx-controls. All studies were multicenter. Common pt eligibility criteria included: diagnosis of mCRC with measurable disease per modified RECIST criteria, age ≥ 18 years, and adequate hematologic, renal, hepatic, and metabolic function. All studies required pts to receive FOLFOX, FOLFIRI, or irinotecan ctx in combination with pmab. Pts received pmab 6.0 mg/kg Q2W with FOLFOX Q2W or FOLFIRI Q2W, or pmab 9.0 mg/kg Q3W with irinotecan Q3W. Results from planned interim analyses are available for 3 studies, and results from the final analysis are available for one study. Results: Among the 4-study safety data, 1213 pts received pmab + ctx; 703 pts received pmab + FOLFIRI, 455 pts received pmab + FOLFOX, and 55 pts received pmab + irinotecan. Approximately 1,200 pts were enrolled in each phase III study, and data are available from 1,003 pts who received pmab + ctx and 997 pts who received ctx alone. All pts in the phase III studies, regardless of treatment group, were included in the pooled, blinded interim analysis sets monitored by the data monitoring committee for each study. Safety results for the two phase II studies of pmab + ctx and two phase III studies of pmab ± ctx are summarized (Table). Conclusions: Phase II data are consistent with expectations, and phase III trials are ongoing. A consistent safety profile was observed across studies. [Table: see text] [Table: see text]

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Self-reported conflicts of interest (sfCOI) of authors and the interpretation of randomized phase III trials (RCT) and related editorials (REd) in cancer research.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.6055 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 6055-6055

Author(s):

Giovanni Mendonca Bariani ◽

Anezka Carvalho Rubin De Celis Ferrari ◽

Paulo Marcelo Hoff ◽

Rachel Riechelmann

Keyword(s):

Cancer Research ◽

Logistic Regression ◽

Conflicts Of Interest ◽

Multivariable Analysis ◽

Phase Iii ◽

Experimental Therapy ◽

Negative Results ◽

Study Results ◽

Phase Iii Trials ◽

Cancer Studies

6055 Background: Growing participation from industry in cancer research has resulted in increased reporting of COI. We aimed to test any association between author’s conclusion and sfCOI in cancer studies. Methods: All RCT and REd published in 6 major cancer journals in a 3.5 year period were selected. Two investigators blinded to COI disclosure independently analyzed each RCT and REd, classifying authors’ conclusions as highly positive, positive, neutral, negative, and highly negative with respect to author’s opinion on the experimental therapy. The agreement rate between investigators for conclusion classification was 90% (consensus was achieved for the remaining 10%). We also collected data on study results, COI and sponsorship. COI was defined as any self-reported financial tie between author and industry except for research funds. Predictors of positive/highly positive conclusions of RCT and of REd were tested separately in logistic regression multivariable models. Results: From Jan 2008 to Oct 2011, 1,485 articles were retrieved: 150 RCT and 140 REd were eligible. Among the RCT, 82 (55%) were positive, and 78 (52%) were entirely or partially funded by industry. Any sfCOI was present in 103 (69%) RCT and in 71 (47%) REd. Conclusions of REd and RCT were: 7.3% and 11.3% highly positive, 42.7% and 57.3% positive, 8.0% and 2.0% neutral, 29.3% and 18.7% negative, and 12.7% and 10.7% highly negative, respectively. Multivariable analysis showed that RCT positive result was the only significant predictor for positive conclusion by RCT authors (OR=109, 95% CI: 21-567; p<0.001). The only factor associated with positive conclusions of REd authors was a positive conclusion by RCT author (OR=42, 95% CI: 7-244; p<0.001). While 64 (43%) RCT reported negative results, 103 (68.7%) RCT authors interpreted studies positively. Logistic regression for discordance between RCT result and RCT conclusion did not find any association with COI. Conclusions: The interpretation of RCT results by authors was not influenced by sfCOI or trial sponsorship. Authors of REd were not influenced by study results or by their sfCOI when discussing cancer RCT.

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Tolerability and activity of combinations of the PI3Kδ inhibitor idelalisib (GS-1101) with rituximab and/or bendamustine in patients with previously treated, indolent non-Hodgkin lymphoma (iNHL): Updated results from a phase I study.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.8500 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 8500-8500 ◽

Cited By ~ 5

Author(s):

John Leonard ◽

Nina D. Wagner-Johnston ◽

Steven E. Coutre ◽

Ian Flinn ◽

Marshall T. Schreeder ◽

...

Keyword(s):

Combination Therapy ◽

Phase I ◽

Phase I Study ◽

Phase Iii ◽

Duration Of Treatment ◽

Non Hodgkin Lymphoma ◽

Highly Active ◽

Study Results ◽

Asco 2012 ◽

Phase Iii Trials

8500 Background: PI3K-delta signaling is critical for activation, proliferation and survival of B cells, and is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective, oral inhibitor of PI3Kδ that has shown considerable monotherapy activity in recurrent iNHL (Kahl, ICML 2011), as well as combination therapy (Fowler, ASCO 2012). Methods: This phase I study evaluated the activity of continuous (48 weeks) idelalisib (Id), 100/150 mg BID, in combination with rituximab (R) (375 mg/m2 weekly x 8 doses) (Id+R), with bendamustine (B) (90 mg/m2 x 2, for 6 cycles) (Id+B), or in combination with R (375 mg/m2 monthly x 6) and B (90 mg/m2 x 2), for 6 cycles (Id+BR). Investigators assessed response according to standard criteria (Cheson 2007). Patients who continued to benefit were able to enroll on an extension study. Results: Study enrolled 78 pts with relapsed/refractory iNHL, with 34 (44%) pts continuing on treatment in the ongoing extension protocol. The 3 cohorts included Id+R (N=30), Id+B (N=34), and Id+BR (N=14). Pts were 67% male, median age [range] of 62 [37E84] years, 41% with refractory disease, 88% stage III/IV, and 36% of FL with high FLIPI scores. The median [range] number of prior therapies was 3 [1E10]. The median [range] duration of treatment was 10.6 [0.5-29.2] months. Overall response rate (ORR) was 63/78 (81%), with 22/78 (28%) CR. The ORR/CR for Id+R was 77%/20%, Id+B was 85%/29%, and Id+BR was 79%/43%. At 20 months, the PFS was 66%. For responders, 73% were progression-free at 20 months. Most common adverse events included (total%/≥G3%) pyrexia (56/4), fatigue (45/4), nausea (41/0), rash (40/8), cough (37/0), diarrhea (36/8), chills (18/0), URI (18/1), and pneumonia (17/15). Lab abnormalities included (total%/≥G3%) ALT/AST elevations (56/17). Conclusions: Idelalisib-based combination therapy is highly active and well tolerated in patients with relapsed/refractory iNHL. These data support further clinical development. Phase III trials evaluating the efficacy of idelalisib in combination with R, or BR in iNHL are ongoing (NCT01732913, NCT01732926). Clinical trial information: NCT01732913, NCT01732929.

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Measurement of malaria vaccine efficacy in phase III trials: Report of a WHO consultation

Vaccine ◽

10.1016/j.vaccine.2007.01.085 ◽

2007 ◽

Vol 25 (28) ◽

pp. 5115-5123 ◽

Cited By ~ 42

Author(s):

Vasee Moorthy ◽

Zarifah Reed ◽

Peter G. Smith

Keyword(s):

Vaccine Efficacy ◽

Malaria Vaccine ◽

Phase Iii ◽

Phase Iii Trials

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The new low-dose transdermal contraceptive system (Twirla®): results from preclinical and Phase III trials

Therapeutic Delivery ◽

10.4155/tde-2021-0001 ◽

2021 ◽

Author(s):

Anita L Nelson

Keyword(s):

Low Dose ◽

Ethinyl Estradiol ◽

Preclinical Study ◽

Phase Iii ◽

Hormonal Contraceptives ◽

Phase Iii Clinical Trials ◽

Estrogen Exposure ◽

Study Results ◽

Phase Iii Trials ◽

Pearl Index

A new low-dose, once-a-week contraceptive transdermal delivery system (TDS) with 2.3-mg ethinyl estradiol (EE) and 2.6-mg levonorgestrel (LNG; Twirla®) has recently been approved by the US FDA for contraception of women with BMI <30 kg/m2. The rationale for developing this new patch, the preclinical study results and the results from two innovative Phase III clinical trials demonstrate that this patch has an acceptable Pearl index (4.3%) for its indicated users and has safety and tolerability comparable to other similar dose oral combined hormonal contraceptives. This new TDS provides an improvement over the existing TDS products, with significantly lower steady-state estrogen exposure, a level equal to that with 30-µg EE containing oral contraceptives.

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Projecting the impact of a two-dose COVID-19 vaccination campaign in Ontario, Canada

10.1101/2020.12.10.20246827 ◽

2020 ◽

Author(s):

Thomas N. Vilches ◽

Kevin Zhang ◽

Robert Van Exan ◽

Joanne M. Langley ◽

Seyed M. Moghadas

Keyword(s):

Vaccine Efficacy ◽

Vaccine Coverage ◽

Vaccination Campaign ◽

Phase Iii ◽

Transmission Model ◽

Time Interval ◽

Population Immunity ◽

Scenario Analyses ◽

Protection Against Infection ◽

The Impact

AbstractBackgroundResults of phase III vaccine clinical trials against COVID-19, although encouraging and well above initial expectations, have only reported on efficacy against disease and its severity. We evaluated the impact of vaccination on COVID-19 outbreak and disease outcomes in Ontario, Canada.MethodsWe used an agent-based transmission model and parameterized it with COVID-19 characteristics, demographics of Ontario, and age-specific clinical outcomes derived from outbreak data. We implemented a two-dose vaccination program, prioritizing healthcare workers and high-risk individuals, with 40% vaccine coverage and vaccine efficacy of 95% against disease. Vaccines were distributed at a rate of 30 doses per day per 10,000 population with a 6-day schedule per week. We projected the impact of vaccination on attack rates, hospitalizations, and deaths. For scenario analyses, we varied the vaccine efficacy against infection, under the assumption of 5% pre-existing population immunity.ResultsWith no protection against infection, a two-dose vaccination campaign with a time interval of 21 days between doses reduced attack rate, hospitalizations, and deaths by 44.6% (95% CrI: 34.5% - 54.3%), 63.4% (95% CrI: 56.1% - 69.9%), and 70.0% (95% CrI: 62.6% - 75.8%), respectively. These reductions were improved with increased vaccine efficacy against infection, with similar estimated ranges in the corresponding scenarios with a 28-day time interval between vaccine doses.ConclusionsVaccination can substantially mitigate ongoing COVID-19 outbreaks, even when vaccines offer limited protection against infection. This impact is founded upon a relatively strong vaccine efficacy against disease and severe outcomes.

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Initial experience with sipuleucel-T (sip-T) in the immediate post-approval setting: The University of Washington (UW) experience.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e15206 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e15206-e15206

Author(s):

James P. Dean ◽

Evan Y. Yu ◽

Suzanne Beauchene ◽

Suzanne P Hall ◽

Celestia S. Higano

Keyword(s):

Initial Therapy ◽

Phase Iii ◽

Institutional Review ◽

Fda Approval ◽

Study Results ◽

Phase Iii Trials ◽

Treatment Paradigm ◽

Institutional Experience ◽

The University ◽

Additional Therapy

e15206 Background: UW has participated in clinical trials of sip-T for over 15 years. After sip-T administration in the 3 phase III trials, patients (pts) did not receive additional therapy until objective progression. However, the course of treatment after administration of sip-T outside the setting of a clinical trial is not defined. In order to better understand our own practices in response to this new clinical scenario, we evaluated our institutional experience with commercial sip-T after FDA approval. Methods: Charts of all pts treated with sip-T at UW with at least 3 mos follow-up were retrospectively reviewed. Pt characteristics and treatments administered during the first 3 mos after sip-T infusion were collected. The institutional review board approved this study. Results: Between June 2010 and Nov 2011, 36 pts with mCRPC were treated with commercial sip-T by 3 different MDs. There were 31 Caucasian, 3 African American, and 2 Asian pts. At diagnosis, Gleason score (# pts) was 3+3 (2), 3+4 (5), 4+3 (7), 4+4 (4), 4+5 (16), 5+5 (2); initial therapy was watchful waiting (1), ADT with brachytherapy [BT] (1), BT with XRT (4), ADT/XRT (6), radical prostatectomy [RP] (9), ADT/RP (1). At the time of sip-T therapy, median age 67.8 yrs (44.2 to 84.5), median PSA 56.0, LDH 179.5, alk phos 77, Hgb 12.7, CTC 2. 3 pts had prior chemotherapy for metastatic disease. 34, 2, and 1 pts received 3, 2, and 1 sip-T infusion(s) respectively. Within the first 3 mos after the last sip-T dose, 29 pts had no significant symptoms and received no additional therapy other than ADT +/- ongoing zoledronic acid or denosumab (27), ketoconazole (1), or nilutamide (1); 7 developed pain and received docetaxel [D] (1), XRT and D (3), XRT (1), nilutatmide/D (1), or cabozantinib (1). 6 pts died a median of 10 months after sip-T; none had received chemotherapy before sip-T therapy. Conclusions: The majority of UW pts (80%) received no additional therapy in the first 3 mos after sip-T while 20% developed pain and were treated with docetaxel or other systemic therapy. What treatments should be given and at what interval after sip-T remains unclear. It is likely that new agents will impact the treatment paradigm after sip-T.

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