RESUMEN
A limitation of current SARS-CoV-2 vaccines is that they provide minimal protection against infection with current Omicron subvariants1,2, although they still provide protection against severe disease. Enhanced mucosal immunity may be required to block infection and onward transmission. Intranasal administration of current vaccines has proven inconsistent3-7, suggesting that alternative immunization strategies may be required. Here we show that intratracheal boosting with a bivalent Ad26-based SARS-CoV-2 vaccine results in substantial induction of mucosal humoral and cellular immunity and near-complete protection against SARS-CoV-2 BQ.1.1 challenge. A total of 40 previously immunized rhesus macaques were boosted with a bivalent Ad26 vaccine by the intramuscular, intranasal and intratracheal routes, or with a bivalent mRNA vaccine by the intranasal route. Ad26 boosting by the intratracheal route led to a substantial expansion of mucosal neutralizing antibodies, IgG and IgA binding antibodies, and CD8+ and CD4+ T cell responses, which exceeded those induced by Ad26 boosting by the intramuscular and intranasal routes. Intratracheal Ad26 boosting also led to robust upregulation of cytokine, natural killer, and T and B cell pathways in the lungs. After challenge with a high dose of SARS-CoV-2 BQ.1.1, intratracheal Ad26 boosting provided near-complete protection, whereas the other boosting strategies proved less effective. Protective efficacy correlated best with mucosal humoral and cellular immune responses. These data demonstrate that these immunization strategies induce robust mucosal immunity, suggesting the feasibility of developing vaccines that block respiratory viral infections.
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Inmunidad Mucosa , Inmunización Secundaria , Macaca mulatta , SARS-CoV-2 , Animales , Humanos , Administración Intranasal , Anticuerpos Neutralizantes/biosíntesis , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/biosíntesis , Anticuerpos Antivirales/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , COVID-19/inmunología , COVID-19/prevención & control , COVID-19/virología , Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/inmunología , Citocinas/inmunología , Inmunidad Mucosa/inmunología , Inmunización Secundaria/métodos , Inmunoglobulina A/inmunología , Inmunoglobulina G/inmunología , Inyecciones Intramusculares , Células Asesinas Naturales/inmunología , Pulmón/inmunología , Macaca mulatta/inmunología , Macaca mulatta/virología , Vacunas de ARNm/administración & dosificación , Vacunas de ARNm/inmunología , SARS-CoV-2/clasificación , SARS-CoV-2/inmunología , Tráquea/inmunología , Tráquea/virologíaAsunto(s)
Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19 , Evasión Inmune , SARS-CoV-2 , Humanos , Anticuerpos Neutralizantes/genética , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/genética , Anticuerpos Antivirales/inmunología , COVID-19/genética , COVID-19/inmunología , COVID-19/virología , Evasión Inmune/genética , Evasión Inmune/inmunología , SARS-CoV-2/genética , SARS-CoV-2/inmunologíaAsunto(s)
COVID-19 , Inmunogenicidad Vacunal , Humanos , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacunas Combinadas/inmunología , Vacunas Combinadas/uso terapéutico , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/uso terapéutico , Inmunogenicidad Vacunal/inmunología , COVID-19/genética , COVID-19/inmunología , COVID-19/prevención & control , COVID-19/virología , Vacunas de ARNmRESUMEN
Current COVID-19 vaccines provide robust protection against severe disease but minimal protection against acquisition of infection. Intramuscularly administered COVID-19 vaccines induce robust serum neutralizing antibodies (NAbs), but their ability to boost mucosal immune responses remains to be determined. In this study, we show that the XBB.1.5 messenger RNA (mRNA) boosters result in increased serum neutralization to multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in humans, including the dominant circulating variant JN.1. In contrast, we found that the XBB.1.5 mRNA booster did not augment mucosal NAbs or mucosal IgA responses, although acute SARS-CoV-2 XBB infection substantially increased mucosal antibody responses. These data demonstrate that current XBB.1.5 mRNA boosters substantially enhance peripheral antibody responses but do not robustly increase mucosal antibody responses. Our data highlight a separation between the peripheral and mucosal immune systems in humans and emphasize the importance of developing next-generation vaccines to augment mucosal immunity to protect against respiratory virus infections.
Asunto(s)
Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Inmunidad Mucosa , Inmunización Secundaria , SARS-CoV-2 , Inmunidad Mucosa/inmunología , Humanos , SARS-CoV-2/inmunología , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , COVID-19/inmunología , COVID-19/prevención & control , COVID-19/virología , Femenino , Vacunación , Inmunoglobulina A/inmunología , Inmunoglobulina A/sangre , ARN Mensajero/genética , ARN Mensajero/metabolismo , Animales , AdultoRESUMEN
The viral vector-based COVID-19 vaccine Ad26.COV2.S has been recommended by the WHO since 2021 and has been administered to over 200 million people. Prior studies have shown that Ad26.COV2.S induces durable neutralizing antibodies (NAbs) that increase in coverage of variants over time, even in the absence of boosting or infection. Here, we studied humoral responses following Ad26.COV2.S vaccination in individuals enrolled in the initial Phase 1/2a trial of Ad26.COV2.S in 2020. Through 8 months post vaccination, serum NAb responses increased to variants, including B.1.351 (Beta) and B.1.617.2 (Delta), without additional boosting or infection. The level of somatic hypermutation, measured by nucleotide changes in the VDJ region of the heavy and light antibody chains, increased in Spike-specific B cells. Highly mutated mAbs from these sequences neutralized more SARS-CoV-2 variants than less mutated comparators. These findings suggest that the increase in NAb breadth over time following Ad26.COV2.S vaccination is mediated by affinity maturation.
RESUMEN
Messenger RNA (mRNA) vaccines were highly effective against the ancestral SARS-CoV-2 strain, but the efficacy of bivalent mRNA boosters against XBB variants was substantially lower. Here, we show limited durability of neutralizing antibody (NAb) responses against XBB variants and isotype switching to immunoglobulin G4 (IgG4) responses following bivalent mRNA boosting. Bivalent mRNA boosting elicited modest XBB.1-, XBB.1.5-, and XBB.1.16-specific NAbs that waned rapidly within 3 months. In contrast, bivalent mRNA boosting induced more robust and sustained NAbs against the ancestral WA1/2020 strain, suggesting immune imprinting. Following bivalent mRNA boosting, serum antibody responses were primarily IgG2 and IgG4 responses with poor Fc functional activity. In contrast, a third monovalent mRNA immunization boosted all isotypes including IgG1 and IgG3 with robust Fc functional activity. These data show substantial immune imprinting for the ancestral spike and isotype switching to IgG4 responses following bivalent mRNA boosting, with important implications for future booster designs and boosting strategies.
Asunto(s)
Formación de Anticuerpos , Inmunoglobulina G , Anticuerpos Neutralizantes , Inmunización , ARN Mensajero/genética , Vacunas de ARNmRESUMEN
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variant BA.2.86 has over 30 mutations in spike compared with BA.2 and XBB.1.5, which raised the possibility that BA.2.86 might evade neutralizing antibodies (NAbs) induced by vaccination or infection. In this study, we show that NAb titers are substantially lower to BA.2.86 compared with BA.2 but are similar or slightly higher than to other current circulating variants, including XBB.1.5, EG.5.1, and FL.1.5.1. Moreover, NAb titers against all these variants were higher in vaccinated individuals with a history of XBB.1.5 infection compared with vaccinated individuals with no history of XBB.1.5 infection, suggesting the potential utility of the monovalent XBB.1.5 mRNA boosters.
Asunto(s)
COVID-19 , Humanos , SARS-CoV-2/genética , Anticuerpos Neutralizantes , Inmunización Secundaria , Anticuerpos AntiviralesRESUMEN
The SARS-CoV-2 Omicron variant has continued to evolve. XBB is a recombinant between two BA.2 sublineages, XBB.1 includes the G252V mutation, and XBB.1.5 includes the G252V and F486P mutations. XBB.1.5 has rapidly increased in frequency and has become the dominant virus in New England. The bivalent mRNA vaccine boosters have been shown to increase neutralizing antibody (NAb) titers to multiple variants, but the durability of these responses remains to be determined. We assessed humoral and cellular immune responses in 30 participants who received the bivalent mRNA boosters and performed assays at baseline prior to boosting, at week 3 after boosting, and at month 3 after boosting. Our data demonstrate that XBB.1.5 substantially escapes NAb responses but not T cell responses after bivalent mRNA boosting. NAb titers to XBB.1 and XBB.1.5 were similar, suggesting that the F486P mutation confers greater transmissibility but not increased immune escape. By month 3, NAb titers to XBB.1 and XBB.1.5 declined essentially to baseline levels prior to boosting, while NAb titers to other variants declined less strikingly.
RESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines demonstrate reduced protection against acquisition of BA.5 subvariant but are still effective against severe disease. However, immune correlates of protection against BA.5 remain unknown. We report the immunogenicity and protective efficacy of vaccine regimens consisting of the vector-based Ad26.COV2.S vaccine and the adjuvanted spike ferritin nanoparticle (SpFN) vaccine against a high-dose, mismatched Omicron BA.5 challenge in macaques. The SpFNx3 and Ad26 + SpFNx2 regimens elicit higher antibody responses than Ad26x3, whereas the Ad26 + SpFNx2 and Ad26x3 regimens induce higher CD8 T cell responses than SpFNx3. The Ad26 + SpFNx2 regimen elicits the highest CD4 T cell responses. All three regimens suppress peak and day 4 viral loads in the respiratory tract, which correlate with both humoral and cellular immune responses. This study demonstrates that both homologous and heterologous regimens involving Ad26.COV2.S and SpFN vaccines provide robust protection against a mismatched BA.5 challenge in macaques.
Asunto(s)
COVID-19 , Nanopartículas , Vacunas , Humanos , Animales , Macaca , Ad26COVS1 , COVID-19/prevención & control , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , FerritinasRESUMEN
Waning immunity following mRNA vaccination and the emergence of SARS-CoV-2 variants has led to reduced mRNA vaccine efficacy against both symptomatic infection and severe disease. Bivalent mRNA boosters expressing the Omicron BA.5 and ancestral WA1/2020 Spike proteins have been developed and approved, because BA.5 is currently the dominant SARS-CoV-2 variant and substantially evades neutralizing antibodies (NAbs). Our data show that BA.5 NAb titers were comparable following monovalent and bivalent mRNA boosters.