The CVnCoV (CureVac) mRNA vaccine for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was recently evaluated in a phase 2b/3 efficacy trial in humans
. CV2CoV is a second-generation mRNA ...vaccine containing non-modified nucleosides but with optimized non-coding regions and enhanced antigen expression. Here we report the results of a head-to-head comparison of the immunogenicity and protective efficacy of CVnCoV and CV2CoV in non-human primates. We immunized 18 cynomolgus macaques with two doses of 12 μg lipid nanoparticle-formulated CVnCoV or CV2CoV or with sham (n = 6 per group). Compared with CVnCoV, CV2CoV induced substantially higher titres of binding and neutralizing antibodies, memory B cell responses and T cell responses as well as more potent neutralizing antibody responses against SARS-CoV-2 variants, including the Delta variant. Moreover, CV2CoV was found to be comparably immunogenic to the BNT162b2 (Pfizer) vaccine in macaques. Although CVnCoV provided partial protection against SARS-CoV-2 challenge, CV2CoV afforded more robust protection with markedly lower viral loads in the upper and lower respiratory tracts. Binding and neutralizing antibody titres were correlated with protective efficacy. These data demonstrate that optimization of non-coding regions can greatly improve the immunogenicity and protective efficacy of a non-modified mRNA SARS-CoV-2 vaccine in non-human primates.
The rapid spread of the SARS-CoV-2 Omicron (B.1.1.529) variant, including in highly vaccinated populations, has raised important questions about the efficacy of current vaccines. In this study, we ...show that the mRNA-based BNT162b2 vaccine and the adenovirus-vector-based Ad26.COV2.S vaccine provide robust protection against high-dose challenge with the SARS-CoV-2 Omicron variant in cynomolgus macaques. We vaccinated 30 macaques with homologous and heterologous prime-boost regimens with BNT162b2 and Ad26.COV2.S. Following Omicron challenge, vaccinated macaques demonstrated rapid control of virus in bronchoalveolar lavage, and most vaccinated animals also controlled virus in nasal swabs. However, 4 vaccinated animals that had moderate Omicron-neutralizing antibody titers and undetectable Omicron CD8+ T cell responses failed to control virus in the upper respiratory tract. Moreover, virologic control correlated with both antibody and T cell responses. These data suggest that both humoral and cellular immune responses contribute to vaccine protection against a highly mutated SARS-CoV-2 variant.
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•Ad26.COV2.S and BNT162b2 led to rapid virologic control following Omicron challenge•Both Omicron-specific antibodies and T cells contributed to protection•Virologic failure correlated with moderate antibodies and negligible CD8+ T cells
Heterologous as well as homologous prime-boosting with the mRNA vaccine BNT162b2 and adenovirus-vector-based Ad26.COV2.S vaccine provides robust protection against SARS-CoV-2 Omicron in cynomolgus macaques, with both humoral and cellular immune responses being critical for overall protection.
Spike-specific neutralizing antibodies (NAbs) are generally considered key correlates of vaccine protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Recently, ...robust vaccine prevention of severe disease with SARS-CoV-2 variants that largely escape NAb responses has been reported, suggesting a role for other immune parameters for virologic control. However, direct data demonstrating a role of CD8
T cells in vaccine protection have not yet been reported. In this study, we show that vaccine-elicited CD8
T cells contribute substantially to virologic control after SARS-CoV-2 challenge in rhesus macaques. We vaccinated 30 macaques with a single immunization of the adenovirus vector-based vaccine Ad26.COV2.S or sham and then challenged them with 5 × 10
median tissue culture infectious dose SARS-CoV-2 B.1.617.2 (Delta) by the intranasal and intratracheal routes. All vaccinated animals were infected by this high-dose challenge but showed rapid virologic control in nasal swabs and bronchoalveolar lavage by day 4 after challenge. However, administration of an anti-CD8α- or anti-CD8β-depleting monoclonal antibody in vaccinated animals before SARS-CoV-2 challenge resulted in higher levels of peak and day 4 virus in both the upper and lower respiratory tracts. These data demonstrate that CD8
T cells contribute substantially to vaccine protection against SARS-CoV-2 replication in macaques.
Ad26.COV2.S has demonstrated durability and clinical efficacy against symptomatic COVID-19 in humans. In this study, we report the correlates of durability of humoral and cellular immune responses in ...20 rhesus macaques immunized with single-shot Ad26.COV2.S and the immunogenicity of a booster shot at 8 to 10 months after the initial immunization. Ad26.COV2.S elicited durable binding and neutralizing antibodies as well as memory B cells and long-lived bone marrow plasma cells. Innate immune responses and bone marrow plasma cell responses correlated with durable antibody responses. After Ad26.COV2.S boost immunization, binding and neutralizing antibody responses against multiple SARS-CoV-2 variants increased 31- to 69-fold and 23- to 43-fold, respectively, compared with preboost concentrations. Antigen-specific B cell and T cell responses also increased substantially after the boost immunization. Boosting with a modified Ad26.COV2.S.351 vaccine expressing the SARS-CoV-2 spike protein from the beta variant led to largely comparable responses with slightly higher beta- and omicron-specific humoral immune responses. These data demonstrate that a late boost with Ad26.COV2.S or Ad26.COV2.S.351 resulted in a marked increase in humoral and cellular immune responses that were highly cross-reactive across multiple SARS-CoV-2 variants in rhesus macaques.
The circadian rhythms of melatonin and body temperature are set to an earlier hour in women than in men, even when the women and men maintain nearly identical and consistent bedtimes and wake times. ...Moreover, women tend to wake up earlier than men and exhibit a greater preference for morning activities than men. Although the neurobiological mechanism underlying this sex difference in circadian alignment is unknown, multiple studies in nonhuman animals have demonstrated a sex difference in circadian period that could account for such a difference in circadian alignment between women and men. Whether a sex difference in intrinsic circadian period in humans underlies the difference in circadian alignment between men and women is unknown. We analyzed precise estimates of intrinsic circadian period collected from 157 individuals (52 women, 105 men; aged 18-74 y) studied in a month-long inpatient protocol designed to minimize confounding influences on circadian period estimation. Overall, the average intrinsic period of the melatonin and temperature rhythms in this population was very close to 24 h 24.15 ± 0.2 h (24 h 9 min ± 12 min). We further found that the intrinsic circadian period was significantly shorter in women 24.09 ± 0.2 h (24 h 5 min ± 12 min) than in men 24.19 ± 0.2 h (24 h 11 min ± 12 min); P < 0.01 and that a significantly greater proportion of women have intrinsic circadian periods shorter than 24.0 h (35% vs. 14%; P < 0.01). The shorter average intrinsic circadian period observed in women may have implications for understanding sex differences in habitual sleep duration and insomnia prevalence.
•We exposed healthy older adults to evening blue-enriched vs. ordinary white light.•Blue-enriched light exposure improved working memory performance the next morning.•This effect was not due to ...changes in circadian timing or sleep quality.•This effect was not due to waking from REM vs. NREM.•Blue-enriched light exposure also increased objective alertness on the wake EEG the next morning.
Exposure to light can have acute alerting and circadian phase-shifting effects. This study investigated the effects of evening exposure to blue-enriched polychromatic white (BEL) vs. polychromatic white light (WL) on sleep inertia dissipation the following morning in older adults.
Ten healthy older adults (average age = 63.3 yrs; 6F) participated in a 13-day study comprising three baseline days, an initial circadian phase assessment, four days with 2-h evening light exposures, a post light exposure circadian phase assessment and three recovery days. Participants were randomized to either BEL or WL of the same irradiance for the four evening light exposures. On the next mornings at 2, 12, 22 and 32 min after each wake time, the participants completed a 90-s digit-symbol substitution test (DSST) to assess working memory, and objective alertness was assessed using a wake EEG recording. DSST and power density from the wake EEG recordings were compared between the two groups.
DSST performance improved with time awake (p < 0.0001) and across study days in both light exposure groups (p < 0.0001). There was no main effect of group, although we observed a significant day x group interaction (p = 0.0004), whereby participants exposed to BEL performed significantly better on the first two mornings after light exposures than participants in WL (post-hoc, p < 0.05). On those days, the BEL group showed higher EEG activity in some of the frequency bins in the sigma and beta range (p < 0.05) on the wake EEG.
Exposure to blue-enriched white light in the evening significantly improved DSST performance the following morning when compared to polychromatic white light. This was associated with a higher level of objective alertness on the wake EEG, but not with changes in sleep or circadian timing.
More than a third of US adults report fewer than 6 hours of sleep a night, making chronic sleep restriction a growing public health concern. Sleep curtailment is associated with an increase in ...industrial accidents, motor vehicle accidents, medical and other occupational errors. Young adults are more vulnerable to acute sleep deprivation than older adults, but less is known about how young vs. older adults respond to the more commonly experienced chronic sleep restriction. To test the hypothesis that young adults are more vulnerable to chronic sleep loss than older adults, we compared data from young and older adults who underwent three weeks of chronic sleep restriction (equivalent to 5.6 hours/24 hours) combined with recurrent circadian disruption in an experiment that enabled us to separate the influences of the sleep-wake homeostatic process, the circadian timing system, and the chronic sleep deficit. We found that while young and older adults reported similar levels of subjective sleepiness, objective measures of sleepiness revealed that young adults were more vulnerable and had more attentional failures than the older adults. These results have important public health implications, particularly related to prevention of sleep-related motor vehicle crashes in young drivers. Further research is needed to understand the neurobiological basis of these age-related differences.
Summary
Older adults have reduced sleep quality compared with younger adults when sleeping at habitual times and greater sleep disruption when their sleep is at adverse times. The purpose of this ...analysis was to investigate how subjective measures of sleep relate to objectively recorded sleep in older subjects scheduled to sleep at all times of day. We analyzed data from 24 healthy older (55–74 years) subjects who took part in a 32‐day inpatient study where polysomnography was recorded each night and subjective sleep was assessed after each scheduled wake time. The study included baseline nights and a forced desynchrony (FD) protocol when the subjects lived on a 20‐h rest activity schedule. Our postsleep questionnaire both included quantitative and qualitative questions about the prior sleep. Under baseline and FD conditions, objective and subjective sleep latency were correlated, subjective sleep duration was related to slow‐wave sleep and wake after sleep onset, subjective sleep quality was related to stage 1 and 2 sleep, and sleepiness and refreshment at wake time were related to duration of premature awakening. During FD, most measures of objective and subjective sleep varied with circadian phase and many additional correlations between objective and subjective sleep were present. Our findings show that when sleeping at habitual times, these healthy older subjects did not perceive their generally poor sleep quality, but under FD conditions where sleep quality changed from day‐to‐day their subjective sleep ratings were more associated with their objective sleep.
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