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In May 2016, the Kenyan Ministry of Health (KMoH) reported an outbreak of chikungunya virus (CHIKV) in Mandera County on the border with Somalia. During this time in Somalia, outbreaks of CHIKV were occurring in the neighboring Bula Hawa region, originating from Mogadishu. In Mandera town, 1,792 cases were detected, and an estimated 50% of the health work force was affected by this virus. A cross-border joint response was coordinated between Kenya and Somalia to control the outbreak.1 This was the first reported outbreak of CHIKV in Kenya since 2004. The previous large CHIKV outbreak in Kenya occurred in Lamu Island in 2004, with an estimated 75% of the population infected.2 The disease also spread to the coastal city of Mombasa by the end of 2004, and further to the Comoros and La Reunion islands, causing large outbreaks in 2005–2006. On La Reunion island, unusual clinical complications were reported in association with CHIKV infection, and viral isolate sequences revealed the presence of an alanine-to-valine mutation in the E1 glycoprotein at position 226 (E1:A226V).3 This specific mutation was shown to confer significant increase in CHIKV infectivity for the Aedes albopictus vector, which was also the dominant mosquito species suspected to be responsible for the transmission of CHIKV on the island of La Reunion.4,5 Since then, the E1:A226V mutation has been observed in many of the genomes in the CHIKV lineage, spreading in the East, Central, and South African region (ECSA lineage), and has been shown to have emerged through convergent evolution in at least four different occasions.6 The remarkable emergence and spread of CHIKV adaptation to the Ae. albopictus vector prompted additional studies on the genetic plasticity of this virus, looking for additional biomarkers associated with virus transmission capacity, fitness, and pathogenicity.6–8 Mutations with the ability to enhance infection in this vector are of increased importance, as Ae. albopictus is rapidly expanding throughout the world.9 The Ae. albopictus mosquito is believed to have originated in Asia and is today most commonly found in east Asia. Aedes albopictus is also common in some parts of South and Southeast Asia, India, and Africa, and it has shown increased spread to regions with lower temperatures, such as southern Europe, southern Brazil, northern China, and the northern United States.9 In Europe, this vector has been associated with autochthonous transmission of CHIKV.10 Although some of the more recent CHIKV outbreaks have been transmitted by Ae. albopictus, most of the CHIKV transmissions in the world are associated with Aedes aegypti. Aedes aegypti is a container-breeding, domesticated mosquito mainly found in urban areas and feeding largely on humans during early and late daytime hours. Aedes aegypti originated from the ancestral zoophilic Ae. aegypti formosus native to Africa. Aedes aegypti now is most common in tropical and subtropical regions, such as Africa, India, Southeast Asia, and Australia.9 Recently, two mutations, E1:K211E and E2:V264A, have been reported in the CHIKV to be associated with increased fitness to Ae. aegypti vectors.11 These two mutations, in the background of the wild-type E1:226A, are believed to increase virus infectivity, dissemination, and transmission in Ae. aegypti, with no impact on virus fitness for the Ae. albopictus vector.6,11 E1:K211E was first observed in genomes sampled in 2006 from the Kerala and Puducherry regions, India, and simultaneous presence of both mutations was first observed in 2009–2010 in Tamil Nadu and Andhra Pradesh, India.12,13 In Kenya, the predominant CHIKV vector is Ae. aegypti, and vector competence studies using local vector populations have shown it is capable of transmitting the virus in this region.14 Given the recent large outbreak of CHIKV in the rural setting of Mandera County, Kenya, we analyzed CHIKV genomes sequenced from this outbreak for the presence of adaptive mutations associated with both Ae. albopictus and Ae. aegypti. Along with estimating origins and the time of emergence of a variant that carried two of these previously reported mutations, we also estimated time and origins of the Mandera CHIKV outbreak. Our results indicate the spread of a CHIKV that carries mutations previously associated with increased fitness for Ae. aegypti in Kenya. We also show that this variant is now connected with new large outbreaks in other regions of the world.

The need for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) next-generation vaccines has been highlighted by the rise of variants of concern (VoCs) and the long-term threat of emerging coronaviruses. Here, we design and characterize four categories of engineered nanoparticle immunogens that recapitulate the structural and antigenic properties of the prefusion SARS-CoV-2 spike (S), S1, and receptor-binding domain (RBD). These immunogens induce robust S binding, ACE2 inhibition, and authentic and pseudovirus neutralizing antibodies against SARS-CoV-2. A spike-ferritin nanoparticle (SpFN) vaccine elicits neutralizing titers (ID50 > 10,000) following a single immunization, whereas RBD-ferritin nanoparticle (RFN) immunogens elicit similar responses after two immunizations and also show durable and potent neutralization against circulating VoCs. Passive transfer of immunoglobulin G (IgG) purified from SpFN- or RFN-immunized mice protects K18-hACE2 transgenic mice from a lethal SARS-CoV-2 challenge. Furthermore, S-domain nanoparticle immunization elicits ACE2-blocking activity and ID50 neutralizing antibody titers >2,000 against SARS-CoV-1, highlighting the broad response elicited by these immunogens., Graphical abstract, Joyce et al. generate four categories of engineered SARS-CoV-2 ferritin nanoparticle immunogens using structure-based vaccine design that recapitulate the prefusion SARS-CoV-2 spike, S1, and RBD. These immunogens induce robust and protective neutralizing antibody responses against SARS-CoV-2 and elicit potent neutralization against variants of concern and the heterologous SARS-CoV-1.

The emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants stresses the continued need for next-generation vaccines that confer broad protection against coronavirus disease 2019 (COVID-19). We developed and evaluated an adjuvanted SARS-CoV-2 Spike Ferritin Nanoparticle (SpFN) vaccine in nonhuman primates (NHPs). High-dose (50µg) SpFN vaccine, given twice within a 28 day interval, induced a Th1-biased CD4 T cell helper response and a peak neutralizing antibody geometric mean titer of 52,773 against wild-type virus, with activity against SARS-CoV-1 and minimal decrement against variants of concern. Vaccinated animals mounted an anamnestic response upon high-dose SARS-CoV-2 respiratory challenge that translated into rapid elimination of replicating virus in their upper and lower airways and lung parenchyma. SpFN’s potent and broad immunogenicity profile and resulting efficacy in NHPs supports its utility as a candidate platform for SARS-like betacoronaviruses.One-Sentence SummaryA SARS-CoV-2 Spike protein ferritin nanoparticle vaccine, co-formulated with a liposomal adjuvant, elicits broad neutralizing antibody responses that exceed those observed for other major vaccines and rapidly protects against respiratory infection and disease in the upper and lower airways and lung tissue of nonhuman primates.

In 2016, a chikungunya virus (CHIKV) outbreak was reported in Mandera, Kenya. This was the first major CHIKV outbreak in the country since the global reemergence of this virus in Kenya in 2004. We collected samples and sequenced viral genomes from this outbreak. All Kenyan genomes contained two mutations, E1:K211E and E2:V264A, recently reported to have an association with increased infectivity, dissemination, and transmission in the

VRC01 broadly neutralizing antibodies (bnAbs) target the CD4-binding site (CD4BS) of the human immunodeficiency virus-1 (HIV-1) envelope glycoprotein (Env). Unlike mature antibodies, corresponding VRC01 germline precursors poorly bind to Env. Immunogen design has mostly relied on glycan removal from trimeric Env constructs and has had limited success in eliciting mature VRC01 bnAbs. To better understand elicitation of such bnAbs, we characterized the inferred germline precursor of VRC01 in complex with a modified trimeric 426c Env by cryo-electron microscopy and a 426c gp120 core by X-ray crystallography, biolayer interferometry, immunoprecipitation, and glycoproteomics. Our results show VRC01 germline antibodies interacted with a wild-type 426c core lacking variable loops 1–3 in the presence and absence of a glycan at position Asn276, with the latter form binding with higher affinity than the former. Interactions in the presence of an Asn276 oligosaccharide could be enhanced upon carbohydrate shortening, which should be considered for immunogen design.

Antigen multimerization on a nanoparticle can result in improved neutralizing antibody responses. A platform that has been successfully used for displaying antigens from a number of different viruses is ferritin, a self-assembling protein nanoparticle that allows the attachment of multiple copies (24 monomers or 8 trimers) of a single antigen. Here, we design two-component ferritin variants that allow the attachment of two different antigens on a single particle in a defined ratio and geometric pattern. The two-component ferritin was specifically designed for trimeric antigens, accepting four trimers per particle for each antigen, and was tested with antigens derived from HIV-1 envelope (Env) and influenza hemagglutinin (HA). Particle formation and the presence of native-like antigen conformation were confirmed through negative-stain electron microscopy and antibody-antigen binding analysis. Immunizations in guinea pigs with two-component ferritin particles, displaying diverse Env, HA, or both antigens, elicited neutralizing antibody responses against the respective viruses. The results provide proof-of-principle for the self-assembly of a two-component nanoparticle as a general technology for multimeric presentation of trimeric antigens.

The potency and breadth of the recently isolated neutralizing human monoclonal antibodies to HIV-1 have stimulated interest in their use to prevent or to treat HIV-1 infection. Due to the antigenically diverse nature of the HIV-1 envelope (Env), no single antibody is highly active against all viral strains. While the physical combination of two broadly neutralizing antibodies (bNAbs) can improve coverage against the majority of viruses, the clinical-grade manufacturing and testing of two independent antibody products are time and resource intensive. In this study, we constructed bispecific immunoglobulins (IgGs) composed of independent antigen-binding fragments with a common Fc region. We developed four different bispecific IgG variants that included antibodies targeting four major sites of HIV-1 neutralization. We show that these bispecific IgGs display features of both antibody specificities and, in some cases, display improved coverage over the individual parental antibodies. All four bispecific IgGs neutralized 94% to 97% of antigenically diverse viruses in a panel of 206 HIV-1 strains. Among the bispecific IgGs tested, VRC07 × PG9-16 displayed the most favorable neutralization profile. It was superior in breadth to either of the individual antibodies, neutralizing 97% of viruses with a median 50% inhibitory concentration (IC 50 ) of 0.055 μg/ml. This bispecific IgG also demonstrated in vivo pharmacokinetic parameters comparable to those of the parental bNAbs when administered to rhesus macaques. These results suggest that IgG-based bispecific antibodies are promising candidates for the prevention and treatment of HIV-1 infection in humans. IMPORTANCE To prevent or treat HIV-1 infection, antibodies must potently neutralize nearly all strains of HIV-1. Thus, the physical combination of two or more antibodies may be needed to broaden neutralization coverage and diminish the possibility of viral resistance. A bispecific antibody that has two different antibody binding arms could potentially display neutralization characteristics better than those of any single parental antibody. Here we show that bispecific antibodies contain the binding specificities of the two parental antibodies and that a single bispecific antibody can neutralize 97% of viral strains with a high overall potency. These findings support the use of bispecific antibodies for the prevention or treatment of HIV-1 infection.