Safety and immunogenicity of a variant-adapted SARS-CoV-2 recombinant protein vaccine with AS03 adjuvant as a booster in adults primed with authorized vaccines: a phase 3, parallel-group study.

Background: In a parallel-group, international, phase 3 study (ClinicalTrials.govNCT04762680), we evaluated prototype (D614) and Beta (B.1.351) variant recombinant spike protein booster vaccines with AS03-adjuvant (CoV2 preS dTM-AS03). Methods: Adults, previously primed with mRNA (BNT162b2, mRNA-1273), adenovirus-vectored (Ad26.CoV2.S, ChAdOx1nCoV-19) or protein (CoV2 preS dTM-AS03 [monovalent D614; MV(D614)]) vaccines were enrolled between 29 July 2021 and 22 February 2022. Participants were stratified by age (18-55 and ≥ 56 years) and received one of the following CoV2 preS dTM-AS03 booster formulations: MV(D614) (n = 1285), MV(B.1.351) (n = 707) or bivalent D614 + B.1.351 (BiV; n = 625). Unvaccinated adults who tested negative on a SARS-CoV-2 rapid diagnostic test (control group, n = 479) received two primary doses, 21 days apart, of MV(D614). Anti-D614G and anti-B.1.351 antibodies were evaluated using validated pseudovirus (lentivirus) neutralization (PsVN) assay 14 days post-booster (day [D]15) in 18-55-year-old BNT162b2-primed participants and compared with those pre-booster (D1) and on D36 in 18-55-year-old controls (primary immunogenicity endpoints). PsVN titers to Omicron BA.1, BA.2 and BA.4/5 subvariants were also evaluated. Safety was evaluated over a 12-month follow-up period. Planned interim analyses are presented up to 14 days post-last vaccination for immunogenicity and over a median duration of 5 months for safety. Findings: All three boosters elicited robust anti-D614G or -B.1.351 PsVN responses for mRNA, adenovirus-vectored and protein vaccine-primed groups. Among BNT162b2-primed adults (18-55 years), geometric means of the individual post-booster versus pre-booster titer ratio (95% confidence interval [CI]) were: for MV (D614), 23.37 (18.58-29.38) (anti-D614G); for MV(B.1.351), 35.41 (26.71-46.95) (anti-B.1.351); and for BiV, 14.39 (11.39-18.28) (anti-D614G) and 34.18 (25.84-45.22 (anti-B.1.351). GMT ratios (98.3% CI) versus post-primary vaccination GMTs in controls, were: for MV(D614) booster, 2.16 (1.69; 2.75) [anti-D614G]; for MV(B.1.351), 1.96 (1.54; 2.50) [anti-B.1.351]; and for BiV, 2.34 (1.84; 2.96) [anti-D614G] and 1.39 (1.09; 1.77) [anti-B.1.351]. All booster formulations elicited cross-neutralizing antibodies against Omicron BA.2 (across priming vaccine subgroups), Omicron BA.1 (BNT162b2-primed participants) and Omicron BA.4/5 (BNT162b2-primed participants and MV D614-primed participants). Similar patterns in antibody responses were observed for participants aged ≥56 years. Reactogenicity tended to be transient and mild-to-moderate severity in all booster groups. No safety concerns were identified. Interpretation: CoV2 preS dTM-AS03 boosters demonstrated acceptable safety and elicited robust neutralizing antibodies against multiple variants, regardless of priming vaccine. Funding: Sanofi and Biomedical Advanced Research and Development Authority (BARDA).

A Feshbach resonance in collisions between triplet ground-state molecules.

Collisional resonances are important tools that have been used to modify interactions in ultracold gases, for realizing previously unknown Hamiltonians in quantum simulations1, for creating molecules from atomic gases2 and for controlling chemical reactions. So far, such resonances have been observed for atom-atom collisions, atom-molecule collisions3-7 and collisions between Feshbach molecules, which are very weakly bound8-10. Whether such resonances exist for ultracold ground-state molecules has been debated owing to the possibly high density of states and/or rapid decay of the resonant complex11-15. Here we report a very pronounced and narrow (25 mG) Feshbach resonance in collisions between two triplet ground-state NaLi molecules. This molecular Feshbach resonance has two special characteristics. First, the collisional loss rate is enhanced by more than two orders of magnitude above the background loss rate, which is saturated at the p-wave universal value, owing to strong chemical reactivity. Second, the resonance is located at a magnetic field where two open channels become nearly degenerate. This implies that the intermediate complex predominantly decays to the second open channel. We describe the resonant loss feature using a model with coupled modes that is analogous to a Fabry-Pérot cavity. Our observations provide strong evidence for the existence of long-lived coherent intermediate complexes even in systems without reaction barriers and open up the possibility of coherent control of chemical reactions.

Immunological non-inferiority and safety of a quadrivalent inactivated influenza vaccine versus two trivalent inactivated influenza vaccines in China: Results from two studies.

WHO UNIVERSAL TRIAL NUMBERS (UTNS): U1111-1174-4615 and U1111-1174-4698. CLINICALTRIALS.GOV: NCT04210349 and NCT03430089.

Immunogenicity and safety of booster CYD-TDV dengue vaccine after alternative primary vaccination schedules in healthy individuals aged 9-50 years: a randomised, controlled, phase 2, non-inferiority study.

BACKGROUND: Dengue is endemic in many countries throughout the tropics and subtropics, and the disease causes substantial morbidity and health-care burdens in these regions. We previously compared antibody responses after one-dose, two-dose, or three-dose primary regimens with the only approved dengue vaccine CYD-TDV (Dengvaxia; Sanofi Pasteur, Lyon, France) in individuals aged 9 years and older with previous dengue exposure. In this study, we assessed the need for a CYD-TDV booster after these primary vaccination regimens. METHODS: In this randomised, controlled, phase 2, non-inferiority study, healthy individuals aged 9-50 years recruited from three sites in Colombia and three sites in the Philippines (excluding those with the usual contraindications to vaccinations) were randomly assigned 1:1:1 via a permuted block method with stratification by site and by age group using an independent voice response system to receive, at 6-month intervals, three doses of CYD-TDV (three-dose group), one dose of placebo followed by two doses of CYD-TDV (two-dose group), or two doses of placebo followed by one dose of CYD-TDV (one-dose group). Participants were also randomly assigned (1:1) to receive a CYD-TDV booster at 1 year or 2 years after the last primary dose. Each CYD-TDV dose was 0·5 mL and administered subcutaneously in the deltoid region of the upper arm. The investigators and sponsor, study staff interacting with the investigators, and participants and their parents or legally acceptable representatives were masked to group assignment. Neutralising antibodies were measured by 50% plaque reduction neutralisation testing, and geometric mean titres (GMTs) were calculated. Due to a change in study protocol, only participants who were dengue seropositive at baseline in the Colombian cohort received a booster vaccination. The primary outcome was to show non-inferiority of the booster dose administered at 1 year or 2 years after the two-dose and three-dose primary regimens; non-inferiority was shown if the lower limit of the two-sided adjusted 95% CI of the between-group (day 28 post-booster dose GMT from the three-dose or two-dose group vs day 28 GMT post-dose three of the three-dose primary regimen [three-dose group]) geometric mean ratio (GMR) was higher than 0·5 for each serotype. Non-inferiority of the 1-year or 2-year booster was shown if all four serotypes achieved non-inferiority. Safety was assessed among all participants who received the booster. This trial is registered with ClinicalTrials.gov, NCT02628444, and is closed to accrual. FINDINGS: Between May 2 and Sept 16, 2016, we recruited and enrolled 1050 individuals who received either vaccine or placebo. Of the 350, 348, and 352 individuals randomly assigned to three-dose, two-dose, and one-dose groups, respectively, 108, 115, and 115 from the Colombian cohort were dengue seropositive at baseline and received a booster; 55 and 53 in the three-dose group received a booster after 1 year and 2 years, respectively, as did 59 and 56 in the two-dose group, and 62 and 53 in the one-dose group. After the three-dose primary schedule, non-inferiority was shown for serotypes 2 (GMR 0·746; 95% CI 0·550-1·010) and 3 (1·040; 0·686-1·570) but not serotypes 1 (0·567; 0·399-0·805) and 4 (0·647; 0·434-0·963) for the 1-year booster, and again for serotypes 2 (0·871; 0·673-1·130) and 3 (1·150; 0·887-1·490) but not serotypes 1 (0·688; 0·479-0·989) and 4 (0·655; 0·471-0·911) for the 2-year booster. Similarly, after the two-dose primary schedule, non-inferiority was shown for serotypes 2 (0·809; 0·505-1·300) and 3 (1·19; 0·732-1·940) but not serotypes 1 (0·627; 0·342-1·150) and 4 (0·499; 0·331-0·754) for the 1-year booster, and for serotype 3 (0·911; 0·573-1·450) but not serotypes 1 (0·889; 0·462-1·710), 2 (0·677; 0·402-1·140), and 4 (0·702; 0·447-1·100) for the 2-year booster. Thus, non-inferiority of the 1-year or 2-year booster was not shown after the three-dose or two-dose primary vaccination regimen in dengue-seropositive participants. No safety concerns occurred with the 1-year or 2-year CYD-TDV booster. INTERPRETATION: CYD-TDV booster 1 year or 2 years after the two-dose or three-dose primary vaccination regimen does not elicit a consistent, meaningful booster effect against all dengue serotypes in participants who are seropositive for dengue at baseline. FUNDING: Sanofi Pasteur. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Control of reactive collisions by quantum interference.

In this study, we achieved magnetic control of reactive scattering in an ultracold mixture of 23Na atoms and 23Na6Li molecules. In most molecular collisions, particles react or are lost near short range with unity probability, leading to the so-called universal rate. By contrast, the Na + NaLi system was shown to have only ~4% loss probability in a fully spin-polarized state. By controlling the phase of the scattering wave function via a Feshbach resonance, we modified the loss rate by more than a factor of 100, from far below to far above the universal limit. The results are explained in analogy with an optical Fabry-Perot resonator by interference of reflections at short and long range. Our work demonstrates quantum control of chemistry by magnetic fields with the full dynamic range predicted by our models.

Humoral and cellular immunogenicity and safety following a booster dose of a tetravalent dengue vaccine 5+ years after completion of the primary series in Singapore: 2-year follow-up of a randomized phase II, placebo-controlled trial.

The tetravalent dengue vaccine (CYD-TDV) is approved for use as a 3-dose series for the prevention of dengue in seropositive individuals ≥9 years. A randomized, placebo-controlled, phase II study of a booster dose of CYD-TDV in individuals who completed the 3-dose schedule >5 years previously (NCT02824198), demonstrated that a booster restored neutralizing antibody titers to post-dose 3 levels. We present additional immunogenicity assessments up to 24 months post-booster, and B- and T-cell responses in a participant subset. Participants aged 9-45 years that had received all three doses of CYD-TDV were randomized 3:1 to receive a booster dose of CYD-TDV (n = 89) or placebo (n = 29). Neutralizing antibody levels at Months 1, 6, 12, and 24 post-booster were assessed by plaque reduction neutralization test. In a subset, B-cell responses were assessed by a fluorescent immunospot assay, and T-cells analyzed by flow cytometry at Days 0, 7, 12, Months 1 and 12. We observed an increase of antibody titers Month 1 post-booster, then a gradual decline to Month 24. In the CYD-TDV booster group, an increase in plasmablasts was seen at Day 7 declining by Day 14, an increase in memory B-cells was observed at Day 28 with no persistence at Month 12. CYD-TDV booster recalled a CD8+ T-cell response, dominated by IFN-γ secretion, which decreased 12 months post-booster. This study showed a short-term increase in antibody titers and then gradual decrease following CYD-TDV booster injection >5 years after primary immunization, and the presence of memory B-cells activated following the booster, but with low persistence.

Immunogenicity and safety of simplified vaccination schedules for the CYD-TDV dengue vaccine in healthy individuals aged 9-50 years (CYD65): a randomised, controlled, phase 2, non-inferiority study.

BACKGROUND: Three doses of the licensed tetravalent dengue vaccine CYD-TDV (Dengvaxia, Sanofi Pasteur, Lyon France) are immunogenic and effective against symptomatic dengue in individuals aged 9 years and older who are dengue seropositive. Previous trials have provided some evidence that antibody responses elicited after just one dose or two doses of CYD-TDV might be similar to those elicited after three doses. We compared antibody responses following one-dose, two-dose, and three-dose vaccination regimens in individuals who were dengue seropositive at baseline up to 1 year after the last injection. METHODS: In this randomised, controlled, phase 2, non-inferiority study (CYD65), healthy individuals aged 9-50 years were recruited from the community in three sites in Colombia and three sites in the Philippines. Participants were randomly assigned (1:1:1), using a permuted block method with stratification by site and age group, to receive, at 6-month intervals (on day 0, month 6, and month 12), three doses of CYD-TDV (three-dose group), one dose of placebo (on day 0) and two doses of CYD-TDV (at months 6 and 12; two-dose group), or two doses of placebo (on day 0 and month 6) and one dose of CYD-TDV (at month 12; one-dose group). Each dose of CYD-TDV was 0·5 mL, administered subcutaneously into the deltoid of the upper arm. Participants, study staff, investigators, and the funder were masked to group assignment. The co-primary endpoints were geometric mean titres (GMTs) of neutralising antibodies against each dengue virus serotype at 28 days and 1 year after the last vaccine injection. After a protocol amendment during the conduct of the study, the original co-primary objectives of non-inferiority of the one-dose and two-dose groups to the three-dose group were altered to include non-inferiority of the two-dose group to the three-dose group only, to be assessed in individuals who were dengue seropositive at baseline. Non-inferiority was shown if the lower limit of the 95% CI for the ratio of GMTs (GMR) at 28 days and 1 year between groups was more than 0·5 for each serotype. The analysis of the coprimary objectives was done in the per-protocol analysis dataset, which included all participants who had been vaccinated, had no protocol deviations, and had a valid serology test result for at least one dengue serotype at 28 days after the third injection. Safety was assessed throughout in all participants who received at least one injection of study drug, regardless of serostatus. This trial is registered with ClinicalTrials.gov, NCT02628444, and is closed to accrual. FINDINGS: Between May 2, 2016, and Sept 16, 2016, we recruited and enrolled 1050 individuals, of whom 1048 received at least one injection and 993 had at least one blood sample taken (full-analysis dataset; 333 in three-dose group, 328 in two-dose group, and 332 in one-dose group). 860 (86·6%) of 993 participants in the full-analysis dataset were dengue seropositive at baseline. Non-inferiority (two dose vs three dose) was shown for each serotype at both 28 days and 1 year among dengue-seropositive participants (number of participants assessed: 272 [two-dose group], 265 [three-dose group] at 28 days; and 190 [two-dose group], 185 [three-dose group] at 1 year). At 28 days after the last injection, neutralising antibody GMTs were 899 (95% CI 752-1075) in the two-dose group versus 822 (700-964) in the three dose group against dengue serotype 1 (GMR 1·09 [95% CI 0·86-1·39]); 869 (754-1002) versus 875 (770-995) against serotype 2 (GMR 0·99 [0·82-1·20]); 599 (524-685) versus 610 (535-694) against serotype 3 (GMR 0·98 [0·82-1·18]); and 510 (453-575) versus 531 (470-601) against serotype 4 (GMR 0·96 [0·81-1·14]). At year 1, GMTs had decreased but remained above baseline for all serotypes: 504 (95% CI 403-630) in the two-dose group versus 490 (398-604) in the three-dose group against serotype 1 (GMR 1·03 [0·76-1·40]); 737 (611-888) versus 821 (704-957) against serotype 2 (GMR 0·90 [0·71-1·14]); 437 (368-519) versus 477 (405-561) against serotype 3 (GMR 0·92 [0·72-1·16]); and 238 (205-277) versus 270 (235-310) against serotype 4 (GMR 0·88 [0·72-1·09]). Reactogenicity profiles were similar across treatment groups. Most unsolicited adverse events after any injection were non-serious and systemic in nature. During the study, 60 serious adverse events were reported in 58 participants (14 in three-dose group, 26 in two-dose group, 18 in one-dose group), mostly infection and infestations or injury, poisoning, and procedural complications. No serious adverse events of special interest or admissions to hospital for dengue occurred. Two deaths occurred, unrelated to study treatment. INTERPRETATION: A two-dose CYD-TDV regimen might be an alternative to the licensed three-dose regimen in individuals who are dengue seropositive at baseline and aged 9 years and older. Vaccination with a reduced number of doses could lead to improved vaccine compliance and coverage, especially in low-resource settings. FUNDING: Sanofi Pasteur.

Collisional cooling of ultracold molecules.

Since the original work on Bose-Einstein condensation1,2, the use of quantum degenerate gases of atoms has enabled the quantum emulation of important systems in condensed matter and nuclear physics, as well as the study of many-body states that have no analogue in other fields of physics3. Ultracold molecules in the micro- and nanokelvin regimes are expected to bring powerful capabilities to quantum emulation4 and quantum computing5, owing to their rich internal degrees of freedom compared to atoms, and to facilitate precision measurement and the study of quantum chemistry6. Quantum gases of ultracold atoms can be created using collision-based cooling schemes such as evaporative cooling, but thermalization and collisional cooling have not yet been realized for ultracold molecules. Other techniques, such as the use of supersonic jets and cryogenic buffer gases, have reached temperatures limited to above 10 millikelvin7,8. Here we show cooling of NaLi molecules to micro- and nanokelvin temperatures through collisions with ultracold Na atoms, with both molecules and atoms prepared in their stretched hyperfine spin states. We find a lower bound on the ratio of elastic to inelastic molecule-atom collisions that is greater than 50-large enough to support sustained collisional cooling. By employing two stages of evaporation, we increase the phase-space density of the molecules by a factor of 20, achieving temperatures as low as 220 nanokelvin. The favourable collisional properties of the Na-NaLi system could enable the creation of deeply quantum degenerate dipolar molecules and raises the possibility of using stretched spin states in the cooling of other molecules.

Immunogenicity and safety of a dengue vaccine given as a booster in Singapore: a randomized Phase II, placebo-controlled trial evaluating its effects 5-6 years after completion of the primary series.

The tetravalent dengue vaccine (CYD-TDV; Dengvaxia®) is administered on a three-dose schedule, 6 months apart in those aged ≥9 years in a number of dengue-endemic countries in Asia and Latin America. In this study, CYD63 (NCT02824198), participants aged 9-45 years at first vaccination, and who had received three doses of CYD-TDV in the CYD28 study more than 5 years previously, were randomized 3:1 to receive a booster CYD-TDV dose (Group 1) or placebo (Group 2). Dengue neutralizing antibody geometric mean titres (PRNT50 GMTs) for each of the four dengue serotypes were assessed in sera collected before and 28 days after booster injections. Non-inferiority of the booster immune response versus that induced after the third dose was demonstrated for each serotype if the lower limit of the two-sided 95% confidence interval (CI) was >0.5 for the GMT ratios (GMTRs) between post-booster CYD-TDV dose and post-dose 3 in Group 1. Overall, 118 participants received CYD-TDV booster or placebo and 116 (98.3%) completed the study; two participants were withdrawn because of noncompliance. GMTs in the booster CYD-TDV group increased across all serotypes post-booster injection by 1.74- (serotype 1) to 3.58-fold (serotype 4). No discernible increases were observed in the placebo group. Non-inferiority was demonstrated for serotypes 1, 3, and 4, but not for serotype 2 (GMTR; 0.603 [95% CI, 0.439- 0.829]). No safety issues were observed. These data show that the CYD-TDV booster given 5 or more years later tended to restore GMTs back to levels observed post-dose 3.

Two-photon spectroscopy of the NaLi triplet ground state.

We employ two-photon spectroscopy to study the vibrational states of the triplet ground state potential (a3Σ+) of the 23Na6Li molecule. Pairs of Na and Li atoms in an ultracold mixture are photoassociated into an excited triplet molecular state, which in turn is coupled to vibrational states of the triplet ground potential. Vibrational state binding energies, line strengths, and potential fitting parameters for the triplet ground a3Σ+ potential are reported. We also observe rotational splitting in the lowest vibrational state.

Photoassociation of ultracold NaLi.

We perform photoassociation spectroscopy in an ultracold 23Na-6Li mixture to study the c3Σ+ excited triplet molecular potential. We observe 50 vibrational states and their substructure to an accuracy of 20 MHz, and provide line strength data from photoassociation loss measurements. An analysis of the vibrational line positions using near-dissociation expansions and a full potential fit is presented. This is the first observation of the c3Σ+ potential, as well as photoassociation in the NaLi system.

Long-Lived Ultracold Molecules with Electric and Magnetic Dipole Moments.

We create fermionic dipolar ^{23}Na^{6}Li molecules in their triplet ground state from an ultracold mixture of ^{23}Na and ^{6}Li. Using magnetoassociation across a narrow Feshbach resonance followed by a two-photon stimulated Raman adiabatic passage to the triplet ground state, we produce 3×10^{4} ground state molecules in a spin-polarized state. We observe a lifetime of 4.6 s in an isolated molecular sample, approaching the p-wave universal rate limit. Electron spin resonance spectroscopy of the triplet state was used to determine the hyperfine structure of this previously unobserved molecular state.