Army liposome formulation containing QS-21 render human monocyte-derived macrophages less permissive to HIV-1 infection by upregulating ABOBEC3A.

Monocyte-derived macrophages (MDM) are highly permissive to HIV-1 infection potentially due to the downregulation of innate factors during the differentiation process. The environmental milieu and innate anti-viral factors which are modulated during macrophage differentiation, have been associated with their increased permissiveness to HIV-1 infection. Here, we demonstrate that the Army Liposome Formulation containing MPLA, and QS-21 (ALFQ) activated MDM that are normally permissive to HIV-1 infection to generate a proinflammatory environment and upregulated anti-viral factors notably APOBEC3A. Induction of APOBEC3A by ALFQ decreased permissiveness to HIV-1 infection, while knockdown of APOBEC3A with APOBEC3AsiRNA resulted in a significant loss in the restriction of HIV-1 infectivity. The liposome formulation ALF55, with identical lipid composition but lacking QS-21 had no effect. Furthermore, the capacity of ALFQ to modulate MDM permissiveness to HIV-1 infection was predominantly mediated by large ALFQ liposomes. Our findings highlight a relationship between innate immune activation, proinflammatory milieu, and upregulation of anti-HIV proteins. Induction of these responses can switch the HIV-1 permissive MDM into a more refractory phenotype.

SARS-CoV-2 ferritin nanoparticle vaccines elicit broad SARS coronavirus immunogenicity.

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.

SARS-CoV-2 ferritin nanoparticle vaccines elicit broad SARS coronavirus immunogenicity.

The need for SARS-CoV-2 next-generation vaccines has been highlighted by the rise of variants of concern (VoC) and the long-term threat of other coronaviruses. Here, we designed and characterized four categories of engineered nanoparticle immunogens that recapitulate the structural and antigenic properties of prefusion Spike (S), S1 and RBD. These immunogens induced robust S-binding, ACE2-inhibition, and authentic and pseudovirus neutralizing antibodies against SARS-CoV-2 in mice. A Spike-ferritin nanoparticle (SpFN) vaccine elicited neutralizing titers more than 20-fold higher than convalescent donor serum, following a single immunization, while RBD-Ferritin nanoparticle (RFN) immunogens elicited similar responses after two immunizations. Passive transfer of IgG purified from SpFN- or RFN-immunized mice protected K18-hACE2 transgenic mice from a lethal SARS-CoV-2 virus challenge. Furthermore, SpFN- and RFN-immunization elicited ACE2 blocking activity and neutralizing ID50 antibody titers >2,000 against SARS-CoV-1, along with high magnitude neutralizing titers against major VoC. These results provide design strategies for pan-coronavirus vaccine development. HIGHLIGHTS: Iterative structure-based design of four Spike-domain Ferritin nanoparticle classes of immunogensSpFN-ALFQ and RFN-ALFQ immunization elicits potent neutralizing activity against SARS-CoV-2, variants of concern, and SARS-CoV-1Passively transferred IgG from immunized C57BL/6 mice protects K18-hACE2 mice from lethal SARS-CoV-2 challenge.