No abstract

The vaccine elicitation of broadly neutralizing antibodies against HIV-1 is a long-sought goal. We previously reported the amino-terminal eight residues of the HIV-1-fusion peptide (FP8) -when conjugated to the carrier protein, keyhole limpet hemocyanin (KLH) -to be capable of inducing broadly neutralizing responses against HIV-1 in animal models. However, KLH is a multi-subunit particle derived from a natural source, and its manufacture as a clinical product remains a challenge. Here we report the preclinical development of recombinant tetanus toxoid heavy chain fragment (rTTHC) linked to FP8 (FP8-rTTHC) as a suitable FP-conjugate vaccine immunogen. We assessed 16 conjugates, made by coupling the 4 most prevalent FP8 sequences with 4 carrier proteins: the aforementioned KLH and rttHc; the H. influenzae protein D (HiD); and the cross-reactive material from diphtheria toxin (CRM197). While each of the 16 FP8-carrier conjugates could elicit HIV-1-neutralizing responses, rTTHC conjugates induced higher FP-directed responses overall. A Sulfo-SIAB linker yielded superior results over an SM(PEG)2 linker but combinations of carriers, conjugation ratio of peptide to carrier, or choice of adjuvant (Adjuplex or Alum) did not significantly impact elicited FP-directed neutralizing responses in mice. Overall, SIAB-linked FP8-rTTHC appears to be a promising vaccine candidate for advancing to clinical assessment.The fusion peptide (FP) site of vulnerability on the HIV-1 envelope (Env) glycoprotein has recently been shown to be a promising vaccine target 1-3 . FP, a hydrophobic region of ~15 residues at the N terminus of the gp41 transmembrane glycoprotein, is an essential component of the HIV entry machinery 4 . FP embeds in the target cell membrane during the pre-hairpin intermediate stage of entry, where it serves to anchor the rearranging viral spike and to facilitate the merging of viral and cell membranes. The N-terminal portion of FP is solvent accessible and recognized by broadly neutralizing antibodies PGT151 5,6 , N123-VRC34.01 3 , and ACS202 7 . Because FP is a short linear peptide, it has low inherent immunogenicity due to its lack of helper T cell epitopes. Coupling peptides to highly immunogenic carrier proteins is a well-established approach for providing T cell help to peptide immunogens [8][9][10][11] . When the N-terminal 6-10 residues of FP are coupled to keyhole limpet hemocyanin (KLH), a standard protein carrier widely used in biotechnology, the resultant FP-KLH conjugate immunogens are able to induce broadly neutralizing FP-directed immune responses in mice, guinea pigs, and rhesus macaques 1,2,12 . Vaccine-induced FP-directed antibodies from mice or NHP neutralize up to 31% or 59%, respectively, of a cross-clade panel of 208 HIV-1 strains 2 .These results (illustrated in Fig. 1a) indicate FP coupled to a carrier protein to be a promising candidate immunogen. However, KLH is a multi-subunit metalloprotein derived from natural sources 13-15 with both sequence and glycan heterogeneity, which pose manufacturin...

For long waves propagating over a randomly uneven seabed, we derive a modified Korteweg-de Vries (KdV) equation including new terms representing the effects of disorder on amplitude attenuation and wave phase. Analytical and numerical results are described for the evolution of a soliton entering a semi-infinite region of disorder, and the fission of new solitons after passing over a finite region of disorder.

The nonlinear long waves generated by a disturbance moving at subcritical, critical and supercritical speed in unbounded shallow water are investigated. The problem is formulated by a new modified generalized Boussinesq equation and solved numerically by an implicit finite-difference algorithm. Three-dimensional upstream solitary waves with significant amplitude are generated with a periodicity by a pressure distribution or slender strut advancing on the free surface. The crestlines of these solitons are almost perfect parabolas with decreasing curvature with respect to time. Behind the disturbance, a complicated, divergent Kelvin-like wave pattern is formed. It is found that, unlike the wave breaking phenomena in a narrow channel at Fh [ges ] 1.2, the three- dimensional upstream solitons form several parabolic water humps and are blocked ahead of the disturbance at supercritical speed in an unbounded domain for large time.

Influenza vaccines could be improved by platforms inducing cross-reactive immunity. Immunodominance of the influenza hemagglutinin (HA) head in currently licensed vaccines impedes induction of cross-reactive neutralizing stem-directed antibodies. A vaccine without the variable HA head domain has the potential to focus the immune response on the conserved HA stem. This first-in-human dose-escalation open-label phase 1 clinical trial (NCT03814720) tested an HA stabilized stem ferritin nanoparticle vaccine (H1ssF) based on the H1 HA stem of A/New Caledonia/20/1999. Fifty-two healthy adults aged 18 to 70 years old enrolled to receive either 20 μg of H1ssF once ( n  = 5) or 60 μg of H1ssF twice ( n  = 47) with a prime-boost interval of 16 weeks. Thirty-five (74%) 60-μg dose participants received the boost, whereas 11 (23%) boost vaccinations were missed because of public health restrictions in the early stages of the COVID-19 pandemic. The primary objective of this trial was to evaluate the safety and tolerability of H1ssF, and the secondary objective was to evaluate antibody responses after vaccination. H1ssF was safe and well tolerated, with mild solicited local and systemic reactogenicity. The most common symptoms included pain or tenderness at the injection site ( n  = 10, 19%), headache ( n  = 10, 19%), and malaise ( n  = 6, 12%). We found that H1ssF elicited cross-reactive neutralizing antibodies against the conserved HA stem of group 1 influenza viruses, despite previous H1 subtype head-specific immunity. These responses were durable, with neutralizing antibodies observed more than 1 year after vaccination. Our results support this platform as a step forward in the development of a universal influenza vaccine.

No abstract

We present an analytical theory of scattering of tide-generated internal gravity waves in a continuously stratified ocean with a randomly rough seabed. Based on a linearized approximation, the idealized case of constant mean sea depth and Brunt–Väisälä frequency is considered. The depth fluctuation is assumed to be a stationary random function of space, characterized by small amplitude and a correlation length comparable to the typical wavelength. For both one- and two-dimensional topographies the effects of scattering on the wave phase over long distances are derived explicitly by the method of multiple scales. For one-dimensional topography, numerical results are compared with Bühler & Holmes-Cerfon (J. Fluid Mech., vol. 678, 2011, pp. 271–293), computed by the method of characteristics. For two-dimensional topography, new results are presented for both statistically isotropic and anisotropic cases.

No abstract