nAb Responses Research Articles

Broad cross neutralizing antibodies against sarbecoviruses generated by SARS-CoV-2 infection and vaccination in humans

The outbreaks of severe acute respiratory syndrome coronavirus (SARS-CoV-1), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2 highlight the need for countermeasures to prevent future coronavirus pandemics. Given the unpredictable nature of spillover events, preparing antibodies with broad coronavirus-neutralizing activity is an ideal proactive strategy. Here, we investigated whether SARS-CoV-2 infection and vaccination could provide cross-neutralizing antibodies (nAbs) against zoonotic sarbecoviruses. We evaluated the cross-neutralizing profiles of plasma and monoclonal antibodies constructed from B cells from coronavirus disease 2019 (COVID-19) convalescents and vaccine recipients; against sarbecoviruses originating from bats, civets, and pangolins; and against SARS-CoV-1 and SARS-CoV-2. We found that the majority of individuals with natural infection and vaccination elicited broad nAb responses to most tested sarbecoviruses, particularly to clade 1b viruses, but exhibited very low cross-neutralization to SARS-CoV-1 in both natural infection and vaccination, and vaccination boosters significantly augmented the magnitude and breadth of nAbs to sarbecoviruses. Of the nAbs, several exhibited neutralization activity against multiple sarbecoviruses by targeting the spike receptor-binding domain (RBD) and competing with angiotensin-converting enzyme 2 (ACE2) binding. SCM12-61 demonstrated exceptional potency, with half-maximal inhibitory concentration (IC50) values of 0.001–0.091 μg/mL against tested sarbecoviruses; while VSM9-12 exhibited remarkable cross-neutralizing breadth against sarbecoviruses and SARS-CoV-2 Omicron subvariants, highlighting the potential of these two nAbs in combating sarbecoviruses and SARS-CoV-2 Omicron subvariants. Collectively, our findings suggest that vaccination with an ancestral SARS-CoV-2 vaccine, in combination with broad nAbs against sarbecoviruses, may provide a countermeasure for preventing further sarbecovirus outbreaks in humans.

Humoral and cellular immune response to AZD1222 /Covishield and BV152/Covaxin COVID-19 vaccines among adults in India

ABSTRACT Several COVID-19 vaccines were developed using different approaches to prevent both symptomatic COVID-19 cases and fatalities. The adults were vaccinated with two doses of AZD1222/Covishield (n = 77) [manufactured by Serum Institute of India Pvt Ltd] vaccine and BV152/Covaxin (n = 99) [manufactured by Bharat Biotech] vaccine. They were assessed for immune response at pre-vaccination, 1 month post first and 6 months post second dose for anti-SARS-CoV-2 IgG antibody, surrogate neutralizing antibody (NAbs), immune phenotypes, antigen specific NK, B and T cell response, their effector functionality by ELISPOT and plasma cytokine profile. Both vaccines elicited enhanced IgG antibody and Nab levels compared to the baseline. BV152/Covaxin, the whole virus inactivated vaccine exhibited higher IgG (70% vs 100%), Nab (90% vs 100%), and robust T cell (31% vs 96%) responses at 6 months post second dose compared to 1 month post first dose justifying the utility of the second dose. Detection of SARS-CoV-2 WV and S1 specific CD4+ central T cell memory response in AZD1222/Covishield vaccinee at 6 months post second dose and higher CD4+ and CD8+ naïve and central memory T cell response in BV152/Covaxin vaccinee at 1 month post first dose indicated the involvement of memory T cells. Persistent IgG and NAb responses along with IgG+B and IgG+memory B cells in AZD1222/Covishield recipients at 6 months post second dose indicated sustained immune memory response. Continued heightened IFN-γ secreting T cell response (ELISPOT) displayed by both the vaccine platforms could serve as a co correlate of protection, further to evaluation in follow up studies. Overall, our data suggest that coordinated functions of humoral and cellular branches of adaptive immunity may pave ways toward protective immunity against COVID-19.

Synergistic evolution: The dynamic adaptation of SARS-CoV-2 and human protective immunity in the real world

SARS-CoV-2 is continually evolving with new variants to evade protective immunity and cause new infections. This study aimed to assess infection-acquired immunity and hybrid immunity against re-infection or severe COVID-19. During 2020-2023, we collected 890 serum samples from individuals infected with SARS-CoV-2 variants including wild type, D614G, Alpha, Delta, BA.1, BA.2, BA.2.76, BA.5.2, BF.7, XBB, and EG.5. The levels of serum neutralizing antibodies (NAbs) against 18 diverse SARS-CoV-2 variants were determined using a bead-based high-throughput broad neutralizing-antibody assay. In the initial wave of the COVID-19 pandemic, >75% of the patients demonstrated robust NAb responses against the ancestral SARS-CoV-2, during a period when vaccines were not yet available. After the emergence of the Omicron variant, the seroprevalence of anti-Omicron NAbs among the patients increased rapidly. By April 2023, when XBB variant was predominant, approximately 80% of the patients demonstrated >50% neutralization against the highly immune-evasive XBB lineages. Three serotypes of SARS-CoV-2, namely non-Omicron, Omicron, and XBB serotypes, were identified, with the strong likelihood of further changes occurring as the virus mutating. Generally, NAbs elicited by a previous serotype could not typically effectively protect against another serotype that emerges later in the evolutionary stages. Our results firstly demonstrated the synergistic evolution between host immunity and SARS-CoV-2 variants in the real world, which would be helpful to develop future vaccines and public health strategies.

Neutralisation Resistance of SARS-CoV-2 Spike-Variants is Primarily Mediated by Synergistic Receptor Binding Domain Substitutions

The evolution of SARS-CoV-2 has led to the emergence of numerous variants of concern (VOCs), marked by changes in the viral spike glycoprotein, the primary target for neutralising antibody (nAb) responses. Emerging VOCs, particularly omicron sub-lineages, show resistance to nAbs induced by prior infection or vaccination. The precise spike protein changes contributing to this resistance remain unclear in infectious cell culture systems. In the present study, a large panel of infectious SARS-CoV-2 mutant viruses, each with spike protein changes found in VOCs, including omicron JN.1 and its derivatives KP.2 and KP.3, was generated using a reverse genetic system. The susceptibility of these viruses to antibody neutralisation was measured using plasma from convalescent and vaccinated individuals. Synergistic roles of combined substitutions in the spike receptor binding domain (RBD) were observed in neutralisation resistance. However, recombinant viruses with the entire spike protein from a specific VOC showed enhanced resistance, indicating that changes outside the RBD are also significant. In silico analyses of spike antibody epitopes suggested changes in neutralisation could be due to altered antibody binding affinities. Assessing ACE2 usage for entry through anti-ACE2 antibody blocking and ACE2 siRNA revealed that omicron BA.2.86 and JN.1 mutant viruses were less dependent on ACE2 for entry. However, surface plasmon resonance analysis showed increased affinity for ACE2 for both BA.2.86 and JN.1 compared to the ancestral spike. This detailed analysis of specific changes in the SARS-CoV-2 spike enhances understanding of coronavirus evolution, particularly regarding neutralising antibody evasion and ACE2 entry receptor dependence.

CoronaVac-vaccinated kidney transplant recipients with hybrid immunity have strong neutralizing responses against Omicron and Mu variants of SARS-CoV-2.

Neutralizing antibody (nAb) responses against SARS-CoV-2 variants after inactivated virus vaccine (CoronaVac) in kidney transplant recipients (KTRs) with or without SARS-CoV-2 infection history remains unclear. We aimed to evaluate the neutralizing antibody responses against emerging SARS-CoV-2 variants after two doses of CoronaVac in these patients. 22.2% of participants had hybrid immunity. Anti-spike IgG antibodies were evidenced in 44% of the patients. nAbs against B.1.111, Mu, and Omicron were detected in 28.5%, 17.9%, and 21.4% of naïve KTRs, respectively. Furthermore, nearly 100% of KTRs with hybrid immunity had nAbs against the variants evaluated. Thus, a significant proportion of infection-naïve KTRs had no detectable nAb titers against Mu and Omicron variants after two doses of the CoronaVac vaccine. However, the nAb titers were significantly higher in patients with hybrid immunity, and it was no association between the immunosuppressive regimen and the seropositivity rate of anti-SARS-CoV-2 neutralizing antibodies. Therefore, hybrid KTRs are protected against COVID-19 by emerging variants able to escape from vaccine-elicited nAbs such as Mu and Omicron.

Assessment of Anti-spike and Neutralizing Antibody Response Against SARS-CoV-2 after Covishield and CovaxinTM Vaccination

ABSTRACT Introduction: This study was conducted to determine total and neutralizing antibody (nAb) titer in individuals at an interval of 2 and 6 months after primary vaccination and after 1 month after administration of booster dose. Materials and Methods: A serum sample was collected from 72 volunteers who were vaccinated with either the Covishield or CovaxinTM vaccine for quantitative estimation of human anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike immunoglobulin G (IgG) antibodies and nAb. nAb against SARS-CoV-2 was detected by GenScript (New Jersey, USA) and was quantitatively estimated by in-house developed enzyme-linked immunosorbent assay (ELISA). Results: Out of 72 study participants, 62.5% and 37.5% were male and female, respectively, and were in the age group of 21–83 years. About 94.44% of study volunteers were vaccinated with the CovishieldTM vaccine. Diabetes mellitus and hypertension were observed in 7.5% of volunteers. The average time interval between two doses of study vaccination was 37 days. Sixty-seven (93.18%), 50 (69.3%), and 69 (96.8%) (N = 72) volunteers elicited good nAb response at the end of 2 months, 6 months, and 1 month post-booster dose vaccination, respectively. Conclusion: Rapid nAb reaction to Spike protein development correlates with viral immunity for Covishield vaccine recipients. Due to the availability of limited data for the CovaxinTM vaccine, we are unable to compare the effectiveness of the two vaccinations, and we are also unable to analyze the vaccine’s efficacy.

An Integrated Signaling Threshold Initiates IgG Response toward Virus-like Immunogens.

Class-switched neutralizing Ab (nAb) production is rapidly induced upon many viral infections. However, due to the presence of multiple components in virions, the precise biochemical and biophysical signals from viral infections that initiate nAb responses remain inadequately defined. Using a reductionist system of synthetic virus-like structures, in this study, we show that a foreign protein on a virion-sized liposome can serve as a stand-alone danger signal to initiate class-switched nAb responses without T cell help or TLR but requires CD19. Introduction of internal nucleic acids (iNAs) obviates the need for CD19, lowers the epitope density (ED) required to elicit the Ab response, and transforms these structures into highly potent immunogens that rival conventional virus-like particles in their ability to elicit strong Ag-specific IgG. As early as day 5 after immunization, structures harboring iNAs and decorated with just a few molecules of surface Ag at doses as low as 100 ng induced all IgG subclasses of Ab in mice and reproduced the IgG2a/2c restriction that is long observed in live viral infections. These findings reveal a shared mechanism for the nAb response in mice. High ED is capable but not necessary for driving Ab secretion. Instead, even a few molecules of surface Ag, when combined with nucleic acids within these structures, can trigger strong IgG production. As a result, the signaling threshold for induction of IgG in individual B cells is set by dual signals originating from both ED on the surface and the presence of iNAs within viral particulate immunogens.

Diversifying selection identified in immune epitopes of bovine coronavirus isolates from Irish cattle.

Bovine betacoronavirus (BoCoV) is a pneumoenteric pathogen of cattle that is closely related to human coronavirus OC43. Vaccines are administered to protect against diseases caused by BoCoV, but knowledge gaps exist with regard to correlates of protection and the effect of immune evasion on driving evolution. In this study, immune epitopes were mapped onto BoCoV structural proteins, including spike and haemagglutinin esterase (HE), and then supported with targeted gene sequencing of Irish clinical isolates and selective pressure analysis. Increased prevalence of diversifying selection and amino acid changes in some mapped immune epitopes suggests that immune escape is selecting for non-synonymous mutations arising in these regions. Selection analysis and sequencing provided increased support for neutralising antibody (nAb) epitopes compared to others, suggesting that nAbs are an important arm of the immune response to BoCoV. Phylogenetic analysis of spike and HE sequences showed that Irish isolates from this study were in the European clade, except for one HE sequence that sat in the Asian/American clade, while the spike gene of this sample was in the European clade. Recombination between a European and an Asian/American isolate would give rise to such a sequence. This study has gathered evidence suggesting that pressure to evade the nAb response is contributing to BoCoV evolution.

A nucleoside-modified mRNA vaccine forming rabies virus-like particle elicits strong cellular and humoral immune responses against rabies virus infection in mice

ABSTRACT Rabies is a lethal zoonotic disease that threatens human health. As the only viral surface protein, the rabies virus (RABV) glycoprotein (G) induces main neutralizing antibody (Nab) responses; however, Nab titre is closely correlated with the conformation of G. Virus-like particles (VLP) formed by the co-expression of RABV G and matrix protein (M) improve retention and antigen presentation, inducing broad, durable immune responses. RABV nucleoprotein (N) can elicit humoral and cellular immune responses. Hence, we developed a series of nucleoside-modified RABV mRNA vaccines encoding wild-type G, soluble trimeric RABV G formed by an artificial trimer motif (tG-MTQ), membrane-anchored prefusion-stabilized G (preG). Furthermore, we also developed RABV VLP mRNA vaccine co-expressing preG and M to generate VLPs, and VLP/N mRNA vaccine co-expressing preG, M, and N. The RABV mRNA vaccines induced higher humoral and cellular responses than inactivated rabies vaccine, and completely protected mice against intracerebral challenge. Additionally, the IgG and Nab titres in RABV preG, VLP and VLP/N mRNA groups were significantly higher than those in G and tG-MTQ groups. A single administration of VLP or VLP/N mRNA vaccines elicited protective Nab responses, the Nab titres were significantly higher than that in inactivated rabies vaccine group at day 7. Moreover, RABV VLP and VLP/N mRNA vaccines showed superior capacities to elicit potent germinal centre, long-lived plasma cell and memory B cell responses, which linked to high titre and durable Nab responses. In summary, our data demonstrated that RABV VLP and VLP/N mRNA vaccines could be promising candidates against rabies.

The Approved Live-Attenuated Chikungunya Virus Vaccine (IXCHIQ®) Elicits Cross-Neutralizing Antibody Breadth Extending to Multiple Arthritogenic Alphaviruses Similar to the Antibody Breadth Following Natural Infection.

The first vaccine against chikungunya virus (CHIKV) was recently licensed in the U.S., Europe, and Canada (brand IXCHIQ®, referred to as VLA1553). Other pathogenic alphaviruses co-circulate with CHIKV and major questions remain regarding the potential of IXCHIQ to confer cross-protection for populations that are exposed to them. Here, we characterized the cross-neutralizing antibody (nAb) responses against heterotypic CHIKV and additional arthritogenic alphaviruses in individuals at one month, six months, and one year post-IXCHIQ vaccination. We characterized nAbs against CHIKV strains LR2006, 181/25, and a 2021 isolate from Tocantins, Brazil, as well as O'nyong-nyong virus (ONNV), Mayaro virus (MAYV), and Ross River virus (RRV). IXCHIQ elicited 100% seroconversion to each virus, with the exception of RRV at 83.3% seroconversion of vaccinees, and cross-neutralizing antibody potency decreased with increasing genetic distance from CHIKV. We compared vaccinee responses to cross-nAbs elicited by natural CHIKV infection in individuals living in the endemic setting of Puerto Rico at 8-9 years post-infection. These data suggest that IXCHIQ efficiently and potently elicits cross-nAb breadth that extends to related alphaviruses in a manner similar to natural CHIKV infection, which may have important implications for individuals that are susceptible to alphavirus co-circulation in regions of potential vaccine rollout.

Minimal Protective Antibody Titers Elicited in Sheep by RVFV MP-12 and arMP-12ΔNSm21/384 Vaccine Candidates

The live attenuated Rift Valley Fever Virus (RVFV) vaccine candidates, RVFV MP-12, and the recombinant derivative, RVFV arMP-12ΔNSm21/384 (MP-12NSm-del), are among the most promising next-generation domestic ruminant vaccine candidates. While both vaccines consistently elicit protective neutralizing Antibodies (nAb) in domestic ruminants, the minimal protective antibody titer is unknown. Therefore, we conducted studies to determine the minimal protective nAb titers elicited in sheep by these vaccines using a mouse model. The approach involved the transfer of sera obtained from sheep vaccinated with the MP-12 and MP-12NSm-del vaccines to 6- to 8-week-old BALB/c mice. The sheep nAb titers ranged from 20 to 640 at the time of transfer. A blood sample was obtained from each mouse 24 hours post-transfer to determine the nAb titer 2 hours before challenging each animal with a lethal dose of virulent RVFV (strain ZH501). All challenged mice were observed daily for 21 days for morbidity and mortality. The lowest nAb titer that protected the animals was interpreted as an estimate of the minimal protective efficacy of the vaccine. The results indicated that nAb titers as low as 10 to 20 elicited by the MP-12 and MP-12NSm-del vaccine candidates in sheep 10 days post-vaccination afforded protection to the mice. However, the nAbs elicited in one sheep by MP-12 before day 10 post-vaccination and ranging in titer from < 5 to 40 only afforded protection to 3 out of 18 mice, and therefore suggested that innate and/or the cellular immune response were also needed for protection during early RVFV infection. The findings further support these RVFV candidate vaccines as potential veterinary vaccines for domestic ruminants and offer a promising BALB/c mouse RVFV challenge model as a surrogate for evaluating the protective nAb response elicited by RVFV vaccines.

Age-dependent decrease of circulating T follicular helper cells correlates with disease severity in elderly patients with COVID-19

Overwhelming evidence has shown that aging is a significant risk factor for COVID-19-related hospitalizations, death and other adverse health outcomes. Particular T cell subsets that susceptible to aging and associated with COVID-19 disease severity requires further elucidation. Our study recruited 57 elderly patients with acute COVID-19 and 27 convalescent donors. Adaptive immunity was assessed across the COVID-19 severity spectrum. Patients underwent age-dependent CD4+ T lymphopenia, preferential loss of circulating T follicular regulatory cells (cTfh) subsets including cTfh-em, cTfh-cm, cTfh1, cTfh2, cTfh17 and circulating T follicular regulatory cells (cTfr), which regulated antibody production through different pathways and correlated with COVID-19 severity, were observed. Moreover, vaccination improved cTfh-cm, cTfh2, cTfr proportion and promoted NAb production. In conclusion, the elderly had gone through age-dependent cTfh subsets deficiency, which impeded NAb production and enabled aggravation of COVID-19 to critical illness, whereas SARS-CoV-2 vaccine inoculation helped to rejuvenate cTfh, cTfr and intensify NAb responses.

Safety and durability of mRNA-1273–induced SARS-CoV-2 immune responses in adolescents: results from the phase 2/3 TeenCOVE trial

Longitudinal changes in vaccination-induced immune response remain inadequately characterized in adolescents. We present long-term safety, immunogenicity, and COVID-19 incidence following a 2-dose mRNA-1273100-μg primary series, and immunogenicity following a single dose of mRNA-1273 50 μg in vaccine-naïve adolescents. TeenCOVE (NCT04649151) Part 1 randomized adolescents (12-17 years) to 2-dose mRNA-1273100 μg (n=2490) or placebo (n=1243) 28 days apart. Subsequently, placebo recipients (n=91) could receive open-label mRNA-1273. Primary objectives included prespecified adverse events through 12 months; secondary objectives were COVID-19 incidence and neutralizing and spike-binding antibodies (nAbs/bAbs) against SARS-CoV-2 (ancestral/variants) through 12 months (study period: December 2020-January 2022). In Part 2, vaccine-naïve adolescents (n=52) received up to 2 doses of mRNA-1273 50 μg; interim analysis included Day 28 (D28) nAbs post-injection 1 in SARS-CoV-2-baseline-positive participants (serologic/virologic evidence of prior infection). In SARS-CoV-2-baseline-negative adolescents (N=369), mRNA-1273 induced robust nAb responses versus baseline (geometric mean concentration [GMC]=11; 95% CI, 11-12) at D28 (1868 [1759-1985]), 6 months (625 [583-670]) and 12 months (550 [490-618]) post-injection 2. Similar bAb responses were observed to alpha/beta/delta/gamma variants; nAb/bAb responses were similar in SARS-CoV-2-baseline-positive adolescents. The 2-dose mRNA-1273100-μg primary series was generally well-tolerated; one case of nonserious, moderate, probable acute myocarditis resolved by 8 days from symptom onset. A single dose of mRNA-1273 50 μg in SARS-CoV-2-baseline-positive adolescents induced higher D28 nAb GMCs against ancestral SARS-CoV-2 than 2-dose mRNA-1273100μg in young adults (geometric mean ratio=4.322 [3.274-5.707]). The overall risk-benefit profile of mRNA-1273 remains favorable in adolescents, with durable 12-month immune responses against SARS-CoV-2 (ancestral/variants). A single mRNA-1273 50-μg injection in vaccine-naïve adolescents elicited robust immune responses against SARS-CoV-2. This project has been funded in whole or in part with federal funds by the Department of Health and Human Services, United States; Administration for Strategic Preparedness and Response, United States; Biomedical Advanced Research and Development Authority, United States, under Contract No. 75A50120C00034. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Department of Health and Human Services or its components.

AEs after COVID-19 vaccination are associated with nAB response

AEs after COVID-19 vaccination are associated with nAB response

COVID-19 Vaccine Side Effects and Long-Term Neutralizing Antibody Response : A Prospective Cohort Study.

Concern about side effects is a common reason for SARS-CoV-2 vaccine hesitancy. To determine whether short-term side effects of SARS-CoV-2 messenger RNA (mRNA) vaccination are associated with subsequent neutralizing antibody (nAB) response. Prospective cohort study. San Francisco Bay Area. Adults who had not been vaccinated against or exposed to SARS-CoV-2, who then received 2 doses of either BNT162b2 or mRNA-1273. Serum nAB titer at 1 month and 6 months after the second vaccine dose. Daily symptom surveys and objective biometric measurements at each dose. 363 participants were included in symptom-related analyses (65.6% female; mean age, 52.4 years [SD, 11.9]), and 147 were included in biometric-related analyses (66.0% female; mean age, 58.8 years [SD, 5.3]). Chills, tiredness, feeling unwell, and headache after the second dose were each associated with 1.4 to 1.6 fold higher nAB at 1 and 6 months after vaccination. Symptom count and vaccination-induced change in skin temperature and heart rate were all positively associated with nAB across both follow-up time points. Each 1 °C increase in skin temperature after dose 2 was associated with 1.8 fold higher nAB 1 month later and 3.1 fold higher nAB 6 months later. The study was conducted in 2021 in people receiving the primary vaccine series, making generalizability to people with prior SARS-CoV-2 vaccination or exposure unclear. Whether the observed associations would also apply for neutralizing activity against non-ancestral SARS-CoV-2 strains is also unknown. Convergent self-report and objective biometric findings indicate that short-term systemic side effects of SARS-CoV-2 mRNA vaccination are associated with greater long-lasting nAB responses. This may be relevant in addressing negative attitudes toward vaccine side effects, which are a barrier to vaccine uptake. National Institute on Aging.

Clinical presentation, viral shedding, and neutralizing antibody responses of mpox cases in South Korea: Single center experience

BackgroundA global mpox outbreak occurred in 2022, and a domestic outbreak started in South Korea in April 2023. This study aimed to evaluate the clinical characteristics, viral shedding, and immune response of mpox in South Korea. MethodsPatients hospitalized with mpox in the National Medical Center between September 2022 and June 2023 were included in this study. Oropharyngeal (OP), anogenital lesion (AL), and skin lesion (SL) swabs and blood samples were collected, and monkeypox virus (MPXV) DNA using real-time polymerase chain reaction (RT-PCR) and culture assays were performed. Neutralizing antibodies (NAbs) against MPXV A.2.1, B.1.1, and B.1.3 were detected using plaque reduction neutralization tests. ResultsEighteen patients were enrolled, of whom 17 (94.4 %) were male, with a median (IQR) age of 32.5 (24–51) years. While nine (50 %) were HIV-infected individuals, none of them revealed CD4+ counts less than 200 cells/μL. MPXV DNA was detected in 87.3 % and 82.7 % of patient's ALs and SLs, respectively, until 2 weeks after symptom onset. While MPXV was isolated for up to 15 days in all three sample types, the culture positivity decreased to 53.8 % and 42.9 % in ALs and SLs after 10 days, respectively, and 28.6 % and 22.2 %, respectively, after 2 weeks from symptom onset. The NAb titers against MPXV A.2.1 were significantly lower than those against B.1.1 and B.1.3. ConclusionsInfectious MPXV was isolated from various anatomical sites up to 15 days after symptom onset. The MPXV NAb response was varied among different lineages, and this implies limited cross-lineage protection.

Minimal Determinants for Lifelong Antiviral Antibody Responses in Mice from a Single Exposure to Virus-like Immunogens at Low Doses.

The durability of an antibody (Ab) response is highly important for antiviral vaccines. However, due to the complex compositions of natural virions, the molecular determinants of Ab durability from viral infection or inactivated viral vaccines have been incompletely understood. Here we used a reductionist system of liposome-based virus-like structures to examine the durability of Abs from primary immune responses in mice. This system allowed us to independently vary fundamental viral attributes and to do so without additional adjuvants to model natural viruses. We show that a single injection of protein antigens (Ags) orderly displayed on a virion-sized liposome is sufficient to induce a long-lived neutralizing Ab (nAb) response. The introduction of internal nucleic acids dramatically modulates the magnitude of Ab responses without an alteration of the long-term kinetic trends. These Abs are characterized by very slow off-rates of ~0.0005 s-1, which emerged as early as day 5 after injection and these off-rates are comparable to that of affinity-matured monoclonal Abs. A single injection of these structures at doses as low as 100 ng led to lifelong nAb production in mice. Thus, a minimal virus-like immunogen can give rise to potent and long-lasting antiviral Abs in a primary response in mice without live infection. This has important implications for understanding both live viral infection and for optimizing vaccine design.

B-cell characteristics define HCV reinfection outcome

In individuals highly exposed to HCV, reinfection is common, suggesting that natural development of sterilising immunity is difficult. In those that are reinfected, some will develop a persistent infection, while a small proportion repeatedly clear the virus, suggesting natural protection is possible. The aim of this study was to characterise immune responses associated with rapid natural clearance of HCV reinfection. Broad neutralising antibodies (nAbs) and Envelope 2 (E2)-specific memory B cell (MBC) responses were examined longitudinally in 15 individuals with varied reinfection outcomes. Broad nAb responses were associated with MBC recall, but not with clearance of reinfection. Strong evidence of antigen imprinting was found, and the B-cell receptor repertoire showed a high level of clonality with ongoing somatic hypermutation of many clones over subsequent reinfection events. Single-cell transcriptomic analyses showed that cleared reinfections featured an activated transcriptomic profile in HCV-specific B cells that rapidly expanded upon reinfection. MBC quality, but not necessarily breadth of nAb responses, is important for protection against antigenically diverse variants, which is encouraging for HCV vaccine development. HCV continues to have a major health burden globally. Limitations in the health infrastructure for diagnosis and treatment, as well as high rates of reinfection, indicate that a vaccine that can protect against chronic HCV infection will greatly complement current efforts to eliminate HCV-related disease. With alternative approaches to testing vaccines, such as controlled human inoculation trials under consideration, we desperately need to identify the correlates of immune protection. In this study, in a small but rare cohort of high-risk injecting drug users who were reinfected multiple times, breadth of neutralisation was not associated with ultimate clearance of the reinfection event. Alternatively, characteristics of the HCV-specific B-cell response associated with B-cell proliferation were. This study indicates that humoral responses are important for protection and suggests that for genetically very diverse viruses, such as HCV, it may be beneficial to look beyond just antibodies as correlates of protection.

Humoral Immune Response to SARS-CoV-2 Spike Protein Receptor-Binding Motif Linear Epitopes.

The worldwide spread of SARS-CoV-2 has led to a significant economic and social burden on a global scale. Even though the pandemic has concluded, apprehension remains regarding the emergence of highly transmissible variants capable of evading immunity induced by either vaccination or prior infection. The success of viral penetration is due to the specific amino acid residues of the receptor-binding motif (RBM) involved in viral attachment. This region interacts with the cellular receptor ACE2, triggering a neutralizing antibody (nAb) response. In this study, we evaluated serum immunogenicity from individuals who received either a single dose or a combination of different vaccines against the original SARS-CoV-2 strain and a mutated linear RBM. Despite a modest antibody response to wild-type SARS-CoV-2 RBM, the Omicron variants exhibit four mutations in the RBM (S477N, T478K, E484A, and F486V) that result in even lower antibody titers. The primary immune responses observed were directed toward IgA and IgG. While nAbs typically target the RBD, our investigation has unveiled reduced seroreactivity within the RBD's crucial subregion, the RBM. This deficiency may have implications for the generation of protective nAbs. An evaluation of S1WT and S2WT RBM peptides binding to nAbs using microscale thermophoresis revealed a higher affinity (35 nM) for the S2WT sequence (GSTPCNGVEGFNCYF), which includes the FNCY patch. Our findings suggest that the linear RBM of SARS-CoV-2 is not an immunodominant region in vaccinated individuals. Comprehending the intricate dynamics of the humoral response, its interplay with viral evolution, and host genetics is crucial for formulating effective vaccination strategies, targeting not only SARS-CoV-2 but also anticipating potential future coronaviruses.

A phase 3 randomized, open-label study evaluating the immunogenicity and safety of concomitant and staggered administration of a live, pentavalent rotavirus vaccine and an inactivated poliomyelitis vaccine in healthy infants in China

ABSTRACT This open-label, randomized, phase 3 study in China (V260-074; NCT04481191) evaluated the immunogenicity and safety of concomitant and staggered administration of three doses of an oral, live, pentavalent rotavirus vaccine (RV5) and three doses of an intramuscular, inactivated poliomyelitis vaccine (IPV) in 400 healthy infants. The primary objective was the non-inferiority of neutralizing antibody (nAb) responses in the concomitant- versus the staggered-use groups. Antibody responses were measured at baseline and 1-month post-dose 3 (PD3). Parents/legal guardians recorded adverse events for 30 or 15 d after study vaccinations in the concomitant-use or staggered-use groups, respectively. At PD3, >98% of participants seroconverted to all three poliovirus types, and the primary objective was met as lower bounds of the two-sided 95% CI for between-group difference in nAb seroconversion percentages ranged from − 4.3% to − 1.6%, for all poliovirus types, p < .001. At PD3, geometric mean titers (GMTs) of nAb responses to poliovirus types 1, 2, and 3 in the concomitant-use group and the staggered-use group were comparable; 100% of participants had nAb titers ≥1:8 and ≥1:64 for all poliovirus types. Anti-rotavirus serotype-specific IgA GMTs and participants with ≥3-fold rise in postvaccination titers from baseline were comparable between groups. Administration of RV5 and IPV was well tolerated with comparable safety profiles in both groups. The immunogenicity of IPV in the concomitant-use group was non-inferior to the staggered-use group and RV5 was immunogenic in both groups. No safety concerns were identified. These data support the concomitant use of RV5 and IPV in healthy Chinese infants.