Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2.

A safe, effective, and scalable vaccine is needed to halt the ongoing SARS-CoV-2 pandemic. We describe the structure-based design of self-assembling protein nanoparticle immunogens that elicit potent and protective antibody responses against SARS-CoV-2 in mice. The nanoparticle vaccines display 60 SARS-CoV-2 spike receptor-binding domains (RBDs) in a highly immunogenic array and induce neutralizing antibody titers 10-fold higher than the prefusion-stabilized spike despite a 5-fold lower dose. Antibodies elicited by the RBD nanoparticles target multiple distinct epitopes, suggesting they may not be easily susceptible to escape mutations, and exhibit a lower binding:neutralizing ratio than convalescent human sera, which may minimize the risk of vaccine-associated enhanced respiratory disease. The high yield and stability of the assembled nanoparticles suggest that manufacture of the nanoparticle vaccines will be highly scalable. These results highlight the utility of robust antigen display platforms and have launched cGMP manufacturing efforts to advance the SARS-CoV-2-RBD nanoparticle vaccine into the clinic.

A close-in giant planet escapes engulfment by its star.

When main-sequence stars expand into red giants, they are expected to engulf close-in planets1-5. Until now, the absence of planets with short orbital periods around post-expansion, core-helium-burning red giants6-8 has been interpreted as evidence that short-period planets around Sun-like stars do not survive the giant expansion phase of their host stars9. Here we present the discovery that the giant planet 8 Ursae Minoris b10 orbits a core-helium-burning red giant. At a distance of only 0.5 AU from its host star, the planet would have been engulfed by its host star, which is predicted by standard single-star evolution to have previously expanded to a radius of 0.7 AU. Given the brief lifetime of helium-burning giants, the nearly circular orbit of the planet is challenging to reconcile with scenarios in which the planet survives by having a distant orbit initially. Instead, the planet may have avoided engulfment through a stellar merger that either altered the evolution of the host star or produced 8 Ursae Minoris b as a second-generation planet11. This system shows that core-helium-burning red giants can harbour close planets and provides evidence for the role of non-canonical stellar evolution in the extended survival of late-stage exoplanetary systems.

A dense 0.1-solar-mass star in a 51-minute-orbital-period eclipsing binary.

Of more than a thousand known cataclysmic variables (CVs), where a white dwarf is accreting from a hydrogen-rich star, only a dozen have orbital periods below 75 minutes1-9. One way to achieve these short periods requires the donor star to have undergone substantial nuclear evolution before interacting with the white dwarf10-14, and it is expected that these objects will transition to helium accretion. These transitional CVs have been proposed as progenitors of helium CVs13-18. However, no known transitional CV is expected to reach an orbital period short enough to account for most of the helium CV population, leaving the role of this evolutionary pathway unclear. Here we report observations of ZTF J1813+4251, a 51-minute-orbital-period, fully eclipsing binary system consisting of a star with a temperature comparable to that of the Sun but a density 100 times greater owing to its helium-rich composition, accreting onto a white dwarf. Phase-resolved spectra, multi-band light curves and the broadband spectral energy distribution allow us to obtain precise and robust constraints on the masses, radii and temperatures of both components. Evolutionary modelling shows that ZTF J1813+4251 is destined to become a helium CV binary, reaching an orbital period under 20 minutes, rendering ZTF J1813+4251 a previously missing link between helium CV binaries and hydrogen-rich CVs.

A 62-minute orbital period black widow binary in a wide hierarchical triple.

Over a dozen millisecond pulsars are ablating low-mass companions in close binary systems. In the original 'black widow', the eight-hour orbital period eclipsing pulsar PSR J1959+2048 (PSR B1957+20)1, high-energy emission originating from the pulsar2 is irradiating and may eventually destroy3 a low-mass companion. These systems are not only physical laboratories that reveal the interesting results of exposing a close companion star to the relativistic energy output of a pulsar, but are also believed to harbour some of the most massive neutron stars4, allowing for robust tests of the neutron star equation of state. Here we report observations of ZTF J1406+1222, a wide hierarchical triple hosting a 62-minute orbital period black widow candidate, the optical flux of which varies by a factor of more than ten. ZTF J1406+1222 pushes the boundaries of evolutionary models5, falling below the 80-minute minimum orbital period of hydrogen-rich systems. The wide tertiary companion is a rare low-metallicity cool subdwarf star, and the system has a Galactic halo orbit consistent with passing near the Galactic Centre, making it a probe of formation channels, neutron star kick physics6 and binary evolution.

Very regular high-frequency pulsation modes in young intermediate-mass stars.

Asteroseismology probes the internal structures of stars by using their natural pulsation frequencies1. It relies on identifying sequences of pulsation modes that can be compared with theoretical models, which has been done successfully for many classes of pulsators, including low-mass solar-type stars2, red giants3, high-mass stars4 and white dwarfs5. However, a large group of pulsating stars of intermediate mass-the so-called δ Scuti stars-have rich pulsation spectra for which systematic mode identification has not hitherto been possible6,7. This arises because only a seemingly random subset of possible modes are excited and because rapid rotation tends to spoil regular patterns8-10. Here we report the detection of remarkably regular sequences of high-frequency pulsation modes in 60 intermediate-mass main-sequence stars, which enables definitive mode identification. The space motions of some of these stars indicate that they are members of known associations of young stars, as confirmed by modelling of their pulsation spectra.

General relativistic orbital decay in a seven-minute-orbital-period eclipsing binary system.

General relativity1 predicts that short-orbital-period binaries emit considerable amounts of gravitational radiation. The upcoming Laser Interferometer Space Antenna2 (LISA) is expected to detect tens of thousands of such systems3 but few have been identified4, of which only one5 is eclipsing-the double-white-dwarf binary SDSS J065133.338+284423.37, which has an orbital period of 12.75 minutes. Here we report the discovery of an eclipsing double-white-dwarf binary system, ZTF J153932.16+502738.8, with an orbital period of 6.91 minutes. This system has an orbit so compact that the entire binary could fit within the diameter of the planet Saturn. The system exhibits a deep eclipse, and a double-lined spectroscopic nature. We see rapid orbital decay, consistent with that expected from general relativity. ZTF J153932.16+502738.8 is a strong source of gravitational radiation close to the peak of LISA's sensitivity, and we expect it to be detected within the first week of LISA observations, once LISA launches in approximately 2034.

A prevalence of dynamo-generated magnetic fields in the cores of intermediate-mass stars.

Magnetic fields play a part in almost all stages of stellar evolution. Most low-mass stars, including the Sun, show surface fields that are generated by dynamo processes in their convective envelopes. Intermediate-mass stars do not have deep convective envelopes, although 10 per cent exhibit strong surface fields that are presumed to be residuals from the star formation process. These stars do have convective cores that might produce internal magnetic fields, and these fields might survive into later stages of stellar evolution, but information has been limited by our inability to measure the fields below the stellar surface. Here we report the strength of dipolar oscillation modes for a sample of 3,600 red giant stars. About 20 per cent of our sample show mode suppression, by strong magnetic fields in the cores, but this fraction is a strong function of mass. Strong core fields occur only in red giants heavier than 1.1 solar masses, and the occurrence rate is at least 50 per cent for intermediate-mass stars (1.6-2.0 solar masses), indicating that powerful dynamos were very common in the previously convective cores of these stars.

The medication kit conundrum: Considerations to enhance safety and efficiency.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

Single-dose replicating RNA vaccine induces neutralizing antibodies against SARS-CoV-2 in nonhuman primates.

The ongoing COVID-19 pandemic, caused by infection with SARS-CoV-2, is having a dramatic and deleterious impact on health services and the global economy. Grim public health statistics highlight the need for vaccines that can rapidly confer protection after a single dose and be manufactured using components suitable for scale-up and efficient distribution. In response, we have rapidly developed repRNA-CoV2S, a stable and highly immunogenic vaccine candidate comprised of an RNA replicon formulated with a novel Lipid InOrganic Nanoparticle (LION) designed to enhance vaccine stability, delivery and immunogenicity. We show that intramuscular injection of LION/repRNA-CoV2S elicits robust anti-SARS-CoV-2 spike protein IgG antibody isotypes indicative of a Type 1 T helper response as well as potent T cell responses in mice. Importantly, a single-dose administration in nonhuman primates elicited antibody responses that potently neutralized SARS-CoV-2. These data support further development of LION/repRNA-CoV2S as a vaccine candidate for prophylactic protection from SARS-CoV-2 infection.

Elicitation of potent neutralizing antibody responses by designed protein nanoparticle vaccines for SARS-CoV-2.

A safe, effective, and scalable vaccine is urgently needed to halt the ongoing SARS-CoV-2 pandemic. Here, we describe the structure-based design of self-assembling protein nanoparticle immunogens that elicit potent and protective antibody responses against SARS-CoV-2 in mice. The nanoparticle vaccines display 60 copies of the SARS-CoV-2 spike (S) glycoprotein receptor-binding domain (RBD) in a highly immunogenic array and induce neutralizing antibody titers roughly ten-fold higher than the prefusion-stabilized S ectodomain trimer despite a more than five-fold lower dose. Antibodies elicited by the nanoparticle immunogens target multiple distinct epitopes on the RBD, suggesting that they may not be easily susceptible to escape mutations, and exhibit a significantly lower binding:neutralizing ratio than convalescent human sera, which may minimize the risk of vaccine-associated enhanced respiratory disease. The high yield and stability of the protein components and assembled nanoparticles, especially compared to the SARS-CoV-2 prefusion-stabilized S trimer, suggest that manufacture of the nanoparticle vaccines will be highly scalable. These results highlight the utility of robust antigen display platforms for inducing potent neutralizing antibody responses and have launched cGMP manufacturing efforts to advance the lead RBD nanoparticle vaccine into the clinic.

Asteroseismology can reveal strong internal magnetic fields in red giant stars.

Internal stellar magnetic fields are inaccessible to direct observations, and little is known about their amplitude, geometry, and evolution. We demonstrate that strong magnetic fields in the cores of red giant stars can be identified with asteroseismology. The fields can manifest themselves via depressed dipole stellar oscillation modes, arising from a magnetic greenhouse effect that scatters and traps oscillation-mode energy within the core of the star. The Kepler satellite has observed a few dozen red giants with depressed dipole modes, which we interpret as stars with strongly magnetized cores. We find that field strengths larger than ~10(5) gauss may produce the observed depression, and in one case we infer a minimum core field strength of ≈10(7) gauss.

Differences between T cell epitopes recognized after immunization and after infection.

Evidence suggests that cellular immune responses play a crucial role in the control of HIV and SIV replication in infected individuals. Several vaccine strategies have therefore targeted these CD8(+) and CD4(+) responses. Whether vaccination induces the same repertoire of responses seen after infection is, however, a key unanswered question in HIV vaccine development. We therefore compared the epitope specificity induced by vaccination to that present postchallenge in the peripheral blood. Intracellular cytokine staining of PBMC stimulated with overlapping 15/20-mer peptides spanning the proteins of SIV were measured after DNA/modified vaccinia Ankara vaccination of eight rhesus macaques. Lymphocytes from 8 animals recognized a total of 39 CD8 epitopes and 41 CD4 epitopes encoded by the vaccine. T cell responses were again monitored after challenge with SIVmac239 to investigate the evolution of these responses. Only 57% of all CD8(+) T cell responses and 19% of all CD4(+) T cell responses present after vaccination were recalled after infection as measured in the peripheral blood. Interestingly, 29 new CD8 epitopes and 5 new CD4 epitopes were recognized by PBMC in the acute phase. These new epitopes were not detected after vaccination, and only some of them were maintained in the chronic phase (33% of CD8 and no CD4 responses). Additionally, 24 new CD8 epitopes and 7 new CD4 epitopes were recognized by PBMC in the chronic phase of infection. The repertoire of the immune response detected in the peripheral blood after immunization substantially differed from the immune response detected in the peripheral blood after infection.