Articles related to Vaccination and Prevention of Covid -19
COVID-19 vaccine strategies must focus on severe disease and global equity
Peter B McIntyre, Rakesh Aggarwal, Ilesh Jani, Jaleela Jawad, Sonali Kochhar, Noni MacDonald, Shabir A Madhi, Ezzeddine Mohsni, Kim Mulholland, Kathleen M Neuzil, Hanna Nohynek, Folake Olayinka, Punnee Pitisuttithum, Andrew J Pollard, Alejandro Cravioto
Abstract: In the panel, we summarise our conclusions and recommendations for global COVID-19 vaccine strategies in 2022. The emergence of delta and now omicron further reinforces the importance of access to COVID-19 vaccines globally and equitably for the health of all. Constrained vaccine supply has driven opportunities for SARS-CoV-2 to mutate to be more infectious. The emergence of omicron has emphasised that further delay in widely delivering at least first doses is fraught with peril for all.
COVID-19 vaccine perceptions and uptake: results from the COVID-19 Global Rheumatology Alliance Vaccine Survey
*Michael Putman, Kevin Kennedy, Emily Sirotich,Jean W Liew, Sebastian E Sattui, Tarin T Moni,Akpabio A Akpabio, Deshire Alpizar-Rodriguez,Saskya Angevare, Richard P Beesley, Francis Berenbaum,Inita Bulina, Yu Pei Eugenia Chock, Richard Conway,Ali Duarte-García, Aman Dev Singh, Eimear Duff,Karen L Durrant, Tamer A Gheita, Catherine L Hill,Richard Howard, Bimba F Hoyer, Evelyn Hsieh, Lina el Kibbi,Adam Kilian, Alfred H J Kim, David F L Liew, Chieh Lo,Elsa F Mateus, Bruce Miller, Serena Mingolla, Michal Nudel,Jasvinder A Singh, Namrata Singh, Manuel F Ugarte-Gil,John Wallace, Kristen J Young, Erick Adrian Zamora-Tehozol,Suleman Bhana, Wendy Costello, Rebecca Grainger,Pedro M Machado, Philip C Robinson, Paul Sufka,Zachary S Wallace, Jinoos Yazdany, Carly Harrison,Maggie J Larché, Mitchell Levine, Gary Foster,Lehana Thabane, Jonathan S Hausmann, Jeffrey A Sparks,Julia F Simard
Abstract: In summary, in this large international survey of people with rheumatic diseases, most people with vaccine hesitancy would consider becoming vaccinated. Data regarding the safety and efficacy of COVID-19 vaccination among people with rheumatic diseases, which is delivered by rheumatologists or patient and professional organisations, might increase vaccine uptake. These findings highlight urgent research and educational priorities to combat vaccine hesitancy in people with rheumatic diseases
SARS-CoV-2 Reinfection Rate and Estimated Effectiveness of the Inactivated Whole Virion Vaccine BBV152 Against Reinfection Among Health Care Workers in New Delhi, India
Sumit Malhotra, MD, 1 Kalaivani Mani, PhD, 2 Rakesh Lodha, MD, 3 Sameer Bakhshi, MD, 4 Vijay Prakash Mathur, MDS, 5 Pooja Gupta, DM, 6 Saurabh Kedia, DM, 7 Jeeva Sankar, DM, 8 Parmeshwar Kumar, MHA, 9 Arvind Kumar, MD, 10 Vineet Ahuja, DM, 7 Subrata Sinha, PhD, 11 Randeep Guleria, DM, 12 and and the COVID Reinfection AIIMS Consortium
Aman Dua, MPH, 1 Shafi Ahmad, MDS, 1 Ramadass Sathiyamoorthy, MD, 1 Ajay Sharma, BSc, 1 Tabbu Sakya, MCA, 1 Vikas Gaur, PhD, 4 Shilpi Chaudhary, PhD, 4 Swetambri Sharma, MSc, 4 Divya Madan, MSc, 7 Anvita Gupta, MSc, 7 Shubi Virmani, MDS, 7 Arti Gupta, MSc, 7 Nidhi Yadav, MSc, 7 Surbhi Sachdeva, MCom, 7 Shilpi Sharma, BA, 7 Sachin Singh, BSc, 7 Abhimanyu Pandey, MPharma, 7 Mukesh Singh, PhD, 7 Divashree Jhurani, MSc, 7 Swarnabha Sarkar, MSc, 13 Amol Kumar Lokade, MDS, 5 Atif Mohammad, MDS, 5 Sabitri Pandit, BTech, 14 Ritu Dubey, MA, 3 Ajay Kumar Singh, MA, 3 Naveen Gohar, BA, 3 Divyansh Soni, MBBS, 15 Arunangshu Bhattacharyya, MBBS, 15 Sabin Rai, MBBS, 15 Snikitha Tummala, MBBS, 15 Ishan Gupta, MBBS, 15 and Sakshi Shukla, MSc 11
A surge of COVID-19 occurred from March to June 2021, in New Delhi, India, linked to the B.1.617.2 (Delta) variant of SARS-CoV-2. COVID-19 vaccines were rolled out for health care workers (HCWs) starting in January 2021.
To assess the incidence density of reinfection among a cohort of HCWs and estimate the effectiveness of the inactivated whole virion vaccine BBV152 against reinfection.
Design, Setting, and Participants:
This was a retrospective cohort study among HCWs working at a tertiary care center in New Delhi, India.
Vaccination with 0, 1, or 2 doses of BBV152.
Main Outcomes and Measures:
The HCWs were categorized as fully vaccinated (with 2 doses and ≥15 days after the second dose), partially vaccinated (with 1 dose or 2 doses with <15 days after the second dose), or unvaccinated. The incidence density of COVID-19 reinfection per 100 person-years was computed, and events from March 3, 2020, to June 18, 2021, were included for analysis. Unadjusted and adjusted hazard ratios (HRs) were estimated using a Cox proportional hazards model. Estimated vaccine effectiveness (1 − adjusted HR) was reported.
Among 15 244 HCWs who participated in the study, 4978 (32.7%) were diagnosed with COVID-19. The mean (SD) age was 36.6 (10.3) years, and 55.0% were male. The reinfection incidence density was 7.26 (95% CI: 6.09-8.66) per 100 person-years (124 HCWs [2.5%], total person follow-up period of 1696 person-years as time at risk). Fully vaccinated HCWs had lower risk of reinfection (HR, 0.14 [95% CI, 0.08-0.23]), symptomatic reinfection (HR, 0.13 [95% CI, 0.07-0.24]), and asymptomatic reinfection (HR, 0.16 [95% CI, 0.05-0.53]) compared with unvaccinated HCWs. Accordingly, among the 3 vaccine categories, reinfection was observed in 60 of 472 (12.7%) of unvaccinated (incidence density, 18.05 per 100 person-years; 95% CI, 14.02-23.25), 39 of 356 (11.0%) of partially vaccinated (incidence density 15.62 per 100 person-years; 95% CI, 11.42-21.38), and 17 of 1089 (1.6%) fully vaccinated (incidence density 2.18 per 100 person-years; 95% CI, 1.35-3.51) HCWs. The estimated effectiveness of BBV152 against reinfection was 86% (95% CI, 77%-92%); symptomatic reinfection, 87% (95% CI, 76%-93%); and asymptomatic reinfection, 84% (95% CI, 47%-95%) among fully vaccinated HCWs. Partial vaccination was not associated with reduced risk of reinfection.
Conclusions and Relevance:
These findings suggest that BBV152 was associated with protection against both symptomatic and asymptomatic reinfection in HCWs after a complete vaccination schedule, when the predominant circulating variant was B.1.617.2.
Ongoing and future COVID-19 vaccine clinical trials: challenges and opportunities
Rafael Dal-Ré, MD,a,* Linda-Gail Bekker, Prof, MD,b Christian Gluud, Prof, MD,c,d Søren Holm, Prof, MD,e Vivekanand Jha, Prof, MD,f,g Gregory A Poland, Prof, MD,h Frits R Rosendaal, Prof, MD,i Brigitte Schwarzer-Daum, Prof, MD,j Esperança Sevene, PhD,k,l Halidou Tinto, Prof, PhD,m Teck Chuan Voo, PhD,n and Nadarajah Sreeharan, MDo
Large-scale deployment of COVID-19 vaccines will seriously affect the ongoing phases 2 and 3 randomised placebo-controlled trials assessing SARS-CoV-2 vaccine candidates. The effect will be particularly acute in high-income countries where the entire adult or older population could be vaccinated by late 2021. Regrettably, only a small proportion of the population in many low-income and middle-income countries will have access to available vaccines. Sponsors of COVID-19 vaccine candidates currently in phase 2 or initiating phase 3 trials in 2021 should consider continuing the research in countries with limited affordability and availability of COVID-19 vaccines. Several ethical principles must be implemented to ensure the equitable, non-exploitative, and respectful conduct of trials in resource-poor settings. Once sufficient knowledge on the immunogenicity response to COVID-19 vaccines is acquired, non-inferiority immunogenicity trials—comparing the immune response of a vaccine candidate to that of an authorised vaccine—would probably be the most common trial design. Until then, placebo-controlled, double-blind, crossover trials will continue to play a role in the development of new vaccine candidates. WHO or the Council for International Organizations of Medical Sciences should define an ethical framework for the requirements and benefits for trial participants and host communities in resource-poor settings that should require commitment from all vaccine candidate sponsors from high-income countries.
Challenges in ensuring global access to COVID-19 vaccines: production, affordability, allocation, and deployment
Olivier J Wouters, PhD,a,* Kenneth C Shadlen, Prof, PhD,b Maximilian Salcher-Konrad, MSc,a Andrew J Pollard, Prof, FMedSci,c,d Heidi J Larson, Prof, PhD,e,f Yot Teerawattananon, PhD,g,h and Mark Jit, Prof, PhDe
The COVID-19 pandemic is unlikely to end until there is global roll-out of vaccines that protect against severe disease and preferably drive herd immunity. Regulators in numerous countries have authorised or approved COVID-19 vaccines for human use, with more expected to be licensed in 2021. Yet having licensed vaccines is not enough to achieve global control of COVID-19: they also need to be produced at scale, priced affordably, allocated globally so that they are available where needed, and widely deployed in local communities. In this Health Policy paper, we review potential challenges to success in each of these dimensions and discuss policy implications. To guide our review, we developed a dashboard to highlight key characteristics of 26 leading vaccine candidates, including efficacy levels, dosing regimens, storage requirements, prices, production capacities in 2021, and stocks reserved for low-income and middle-income countries. We use a traffic-light system to signal the potential contributions of each candidate to achieving global vaccine immunity, highlighting important trade-offs that policy makers need to consider when developing and implementing vaccination programmes. Although specific datapoints are subject to change as the pandemic response progresses, the dashboard will continue to provide a useful lens through which to analyse the key issues affecting the use of COVID-19 vaccines. We also present original data from a 32-country survey (n=26 758) on potential acceptance of COVID-19 vaccines, conducted from October to December, 2020. Vaccine acceptance was highest in Vietnam (98%), India (91%), China (91%), Denmark (87%), and South Korea (87%), and lowest in Serbia (38%), Croatia (41%), France (44%), Lebanon (44%), and Paraguay (51%).
Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: a double-blind, randomised, phase 1 trial
Raches Ella, MBBS,a Krishna Mohan Vadrevu, PhD,a,* Harsh Jogdand, DVM,a Sai Prasad, MSc,a Siddharth Reddy, MSc,a Vamshi Sarangi, BSc,a Brunda Ganneru, PhD,a Gajanan Sapkal, PhD,b Pragya Yadav, PhD,b Priya Abraham, PhD,b Samiran Panda, MD,c Nivedita Gupta, MD,c Prabhakar Reddy, MD,d Savita Verma, PhD,e Sanjay Kumar Rai, MD,f Chandramani Singh, MD,g Sagar Vivek Redkar, MD,h Chandra Sekhar Gillurkar, MD,i Jitendra Singh Kushwaha, MD,j Satyajit Mohapatra, MD,k Venkat Rao, MD,l Randeep Guleria, MD,f Krishna Ella, PhD,a and Balram Bhargava, MDc
To mitigate the effects of COVID-19, a vaccine is urgently needed. BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine formulated with a toll-like receptor 7/8 agonist molecule adsorbed to alum (Algel-IMDG) or alum (Algel).
We did a double-blind, multicentre, randomised, controlled phase 1 trial to assess the safety and immunogenicity of BBV152 at 11 hospitals across India. Healthy adults aged 18–55 years who were deemed healthy by the investigator were eligible. Individuals with positive SARS-CoV-2 nucleic acid and/or serology tests were excluded. Participants were randomly assigned to receive either one of three vaccine formulations (3 μg with Algel-IMDG, 6 μg with Algel-IMDG, or 6 μg with Algel) or an Algel only control vaccine group. Block randomisation was done with a web response platform. Participants and investigators were masked to treatment group allocation. Two intramuscular doses of vaccines were administered on day 0 (the day of randomisation) and day 14. Primary outcomes were solicited local and systemic reactogenicity events at 2 h and 7 days after vaccination and throughout the full study duration, including serious adverse events. Secondary outcome was seroconversion (at least four-fold increase from baseline) based on wild-type virus neutralisation. Cell-mediated responses were evaluated by intracellular staining and ELISpot. The trial is registered at ClinicalTrials.gov (NCT04471519).
Between July 13 and 30, 2020, 827 participants were screened, of whom 375 were enrolled. Among the enrolled participants, 100 each were randomly assigned to the three vaccine groups, and 75 were randomly assigned to the control group (Algel only). After both doses, solicited local and systemic adverse reactions were reported by 17 (17%; 95% CI 10·5–26·1) participants in the 3 μg with Algel-IMDG group, 21 (21%; 13·8–30·5) in the 6 μg with Algel-IMDG group, 14 (14%; 8·1–22·7) in the 6 μg with Algel group, and ten (10%; 6·9–23·6) in the Algel-only group. The most common solicited adverse events were injection site pain (17 [5%] of 375 participants), headache (13 [3%]), fatigue (11 [3%]), fever (nine [2%]), and nausea or vomiting (seven [2%]). All solicited adverse events were mild (43 [69%] of 62) or moderate (19 [31%]) and were more frequent after the first dose. One serious adverse event of viral pneumonitis was reported in the 6 μg with Algel group, unrelated to the vaccine. Seroconversion rates (%) were 87·9, 91·9, and 82·8 in the 3 μg with Algel-IMDG, 6 μg with Algel-IMDG, and 6 μg with Algel groups, respectively. CD4+ and CD8+ T-cell responses were detected in a subset of 16 participants from both Algel-IMDG groups.
BBV152 led to tolerable safety outcomes and enhanced immune responses. Both Algel-IMDG formulations were selected for phase 2 immunogenicity trials. Further efficacy trials are warranted.
Bharat Biotech International.
Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: interim results from a double-blind, randomised, multicentre, phase 2 trial, and 3-month follow-up of a double-blind, randomised phase 1 trial
Raches Ella, MBBS,a Siddharth Reddy, MSc,a Harsh Jogdand, DVM,a Vamshi Sarangi, BSc,a Brunda Ganneru, PhD,a Sai Prasad, MBA,a Dipankar Das, PhD,a Dugyala Raju, PhD,a Usha Praturi, MSc,a Gajanan Sapkal, PhD,b Pragya Yadav, PhD,b Prabhakar Reddy, MD,c Savita Verma, MD,d Chandramani Singh, MD,e Sagar Vivek Redkar, MD,f Chandra Sekhar Gillurkar, MD,g Jitendra Singh Kushwaha, MD,h Satyajit Mohapatra, MD,i Amit Bhate, MD,j Sanjay Rai, MD,k Samiran Panda, MD,l Priya Abraham, PhD,b Nivedita Gupta, MD,l Krishna Ella, PhD,a Balram Bhargava, MD,l and Krishna Mohan Vadrevu, PhDa,*
BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine (3 μg or 6 μg) formulated with a toll-like receptor 7/8 agonist molecule (IMDG) adsorbed to alum (Algel). We previously reported findings from a double-blind, multicentre, randomised, controlled phase 1 trial on the safety and immunogenicity of three different formulations of BBV152 (3 μg with Algel-IMDG, 6 μg with Algel-IMDG, or 6 μg with Algel) and one Algel-only control (no antigen), with the first dose administered on day 0 and the second dose on day 14. The 3 μg and 6 μg with Algel-IMDG formulations were selected for this phase 2 study. Herein, we report interim findings of the phase 2 trial on the immunogenicity and safety of BBV152, with the first dose administered on day 0 and the second dose on day 28.
We did a double-blind, randomised, multicentre, phase 2 clinical trial to evaluate the immunogenicity and safety of BBV152 in healthy adults and adolescents (aged 12–65 years) at nine hospitals in India. Participants with positive SARS-CoV-2 nucleic acid and serology tests were excluded. Participants were randomly assigned (1:1) to receive either 3 μg with Algel-IMDG or 6 μg with Algel-IMDG. Block randomisation was done by use of an interactive web response system. Participants, investigators, study coordinators, study-related personnel, and the sponsor were masked to treatment group allocation. Two intramuscular doses of vaccine were administered on day 0 and day 28. The primary outcome was SARS-CoV-2 wild-type neutralising antibody titres and seroconversion rates (defined as a post-vaccination titre that was at least four-fold higher than the baseline titre) at 4 weeks after the second dose (day 56), measured by use of the plaque-reduction neutralisation test (PRNT50) and the microneutralisation test (MNT50). The primary outcome was assessed in all participants who had received both doses of the vaccine. Cell-mediated responses were a secondary outcome and were assessed by T-helper-1 (Th1)/Th2 profiling at 2 weeks after the second dose (day 42). Safety was assessed in all participants who received at least one dose of the vaccine. In addition, we report immunogenicity results from a follow-up blood draw collected from phase 1 trial participants at 3 months after they received the second dose (day 104). This trial is registered at ClinicalTrials.gov, NCT04471519.
Between Sept 5 and 12, 2020, 921 participants were screened, of whom 380 were enrolled and randomly assigned to the 3 μg with Algel-IMDG group (n=190) or 6 μg with Algel-IMDG group (n=190). Geometric mean titres (GMTs; PRNT50) at day 56 were significantly higher in the 6 μg with Algel-IMDG group (197·0 [95% CI 155·6–249·4]) than the 3 μg with Algel-IMDG group (100·9 [74·1–137·4]; p=0·0041). Seroconversion based on PRNT50 at day 56 was reported in 171 (92·9% [95% CI 88·2–96·2] of 184 participants in the 3 μg with Algel-IMDG group and 174 (98·3% [95·1–99·6]) of 177 participants in the 6 μg with Algel-IMDG group. GMTs (MNT50) at day 56 were 92·5 (95% CI 77·7–110·2) in the 3 μg with Algel-IMDG group and 160·1 (135·8–188·8) in the 6 μg with Algel-IMDG group. Seroconversion based on MNT50 at day 56 was reported in 162 (88·0% [95% CI 82·4–92·3]) of 184 participants in the 3 μg with Algel-IMDG group and 171 (96·6% [92·8–98·8]) of 177 participants in the 6 μg with Algel-IMDG group. The 3 μg with Algel-IMDG and 6 μg with Algel-IMDG formulations elicited T-cell responses that were biased to a Th1 phenotype at day 42. No significant difference in the proportion of participants who had a solicited local or systemic adverse reaction in the 3 μg with Algel-IMDG group (38 [20·0%; 95% CI 14·7–26·5] of 190) and the 6 μg with Algel-IMDG group (40 [21·1%; 15·5–27·5] of 190) was observed on days 0–7 and days 28–35; no serious adverse events were reported in the study. From the phase 1 trial, 3-month post-second-dose GMTs (MNT50) were 39·9 (95% CI 32·0–49·9) in the 3μg with Algel-IMDG group, 69·5 (53·7–89·9) in the 6 μg with Algel-IMDG group, 53·3 (40·1–71·0) in the 6 μg with Algel group, and 20·7 (14·5–29·5) in the Algel alone group.
In the phase 1 trial, BBV152 induced high neutralising antibody responses that remained elevated in all participants at 3 months after the second vaccination. In the phase 2 trial, BBV152 showed better reactogenicity and safety outcomes, and enhanced humoral and cell-mediated immune responses compared with the phase 1 trial. The 6 μg with Algel-IMDG formulation has been selected for the phase 3 efficacy trial.
Bharat Biotech International.
Cytotoxic T-lymphocyte elicited vaccine against SARS-CoV-2 employing immunoinformatics framework
Neeraj Kumar, Nikita Admane, [...], and Abhinav Grover
Development of effective counteragents against the novel coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains, requires clear insights and information for understanding the immune responses associated with it. This global pandemic has pushed the healthcare system and restricted the movement of people and succumbing of the available therapeutics utterly warrants the development of a potential vaccine to contest the deadly situation. In the present study, highly efficacious, immunodominant cytotoxic T-lymphocyte (CTL) epitopes were predicted by advanced immunoinformatics assays using the spike glycoprotein of SARS-CoV2, generating a robust and specific immune response with convincing immunological parameters (Antigenicity, TAP affinity, MHC binder) engendering an efficient viral vaccine. The molecular docking studies show strong binding of the CTL construct with MHC-1 and host membrane specific TLR2 receptors. The molecular dynamics simulation in an explicit system confirmed the stable and robust binding of CTL epitope with TLR2. Steep magnitude RMSD variation and compelling residual fluctuations existed in terminal residues and various loops of the β linker segments of TLR2-epitope (residues 105-156 and 239-254) to about 0.4 nm. The reduced Rg value (3.3 nm) and stagnant SASA analysis (275 nm/S2/N after 8 ns and 5 ns) for protein surface and its orientation in the exposed and buried regions suggests more compactness due to the strong binding interaction of the epitope. The CTL vaccine candidate establishes a high capability to elicit the critical immune regulators, like T-cells and memory cells as proven by the in silico immunization assays and can be further corroborated through in vitro and in vivo assays.
Subject terms: Computational biology and bioinformatics, Biophysics
Public health impact of delaying second dose of BNT162b2 or mRNA-1273 covid-19 vaccine: simulation agent based modeling study
Santiago Romero-Brufau, assistant professor of medicine and healthcare systems engineering, instructor,1,2 Ayush Chopra, masters student,3 Alex J Ryu, assistant professor of medicine,1 Esma Gel, associate professor,4 Ramesh Raskar, associate professor,3 Walter Kremers, associate professor biostatistics,5 Karen S Anderson, professor,4 Jayakumar Subramanian, senior research scientist,6 Balaji Krishnamurthy, principal scientist and director,6 Abhishek Singh, masters student,3 Kalyan Pasupathy, associate professor of health care systems engineering,5 Yue Dong, assistant professor,7 John C O’Horo, associate professor of medicine,1 Walter R Wilson, professor of medicine,1 Oscar Mitchell, fellow, pulmonary and critical care medicine,8 and Thomas C Kingsley, assistant professor of medicine 1
To estimate population health outcomes with delayed second dose versus standard schedule of SARS-CoV-2 mRNA vaccination.
Simulation agent based modeling study.
Simulated population based on real world US county.
The simulation included 100 000 agents, with a representative distribution of demographics and occupations. Networks of contacts were established to simulate potentially infectious interactions though occupation, household, and random interactions.
Simulation of standard covid-19 vaccination versus delayed second dose vaccination prioritizing the first dose. The simulation runs were replicated 10 times. Sensitivity analyses included first dose vaccine efficacy of 50%, 60%, 70%, 80%, and 90% after day 12 post-vaccination; vaccination rate of 0.1%, 0.3%, and 1% of population per day; assuming the vaccine prevents only symptoms but not asymptomatic spread (that is, non-sterilizing vaccine); and an alternative vaccination strategy that implements delayed second dose for people under 65 years of age, but not until all those above this age have been vaccinated.
Main outcome measures
Cumulative covid-19 mortality, cumulative SARS-CoV-2 infections, and cumulative hospital admissions due to covid-19 over 180 days.
Over all simulation replications, the median cumulative mortality per 100 000 for standard dosing versus delayed second dose was 226 v 179, 233 v 207, and 235 v 236 for 90%, 80%, and 70% first dose efficacy, respectively. The delayed second dose strategy was optimal for vaccine efficacies at or above 80% and vaccination rates at or below 0.3% of the population per day, under both sterilizing and non-sterilizing vaccine assumptions, resulting in absolute cumulative mortality reductions between 26 and 47 per 100 000. The delayed second dose strategy for people under 65 performed consistently well under all vaccination rates tested.
A delayed second dose vaccination strategy, at least for people aged under 65, could result in reduced cumulative mortality under certain conditions.