Seasonal human coronavirus antibodies are boosted upon SARS-CoV-2 infection but not associated with protection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread within the human population. Although SARS-CoV-2 is a novel coronavirus, most humans had been previously exposed to other antigenically distinct common seasonal human coronaviruses (hCoVs) before the coronavirus disease 2019 (COVID-19) pandemic. Here, we quantified levels of SARS-CoV-2-reactive antibodies and hCoV-reactive antibodies in serum samples collected from 431 humans before the COVID-19 pandemic. We then quantified pre-pandemic antibody levels in serum from a separate cohort of 251 individuals who became PCR-confirmed infected with SARS-CoV-2. Finally, we longitudinally measured hCoV and SARS-CoV-2 antibodies in the serum of hospitalized COVID-19 patients. Our studies indicate that most individuals possessed hCoV-reactive antibodies before the COVID-19 pandemic. We determined that ∼20% of these individuals possessed non-neutralizing antibodies that cross-reacted with SARS-CoV-2 spike and nucleocapsid proteins. These antibodies were not associated with protection against SARS-CoV-2 infections or hospitalizations, but they were boosted upon SARS-CoV-2 infection.

Deciphering factors linked with reduced SARS-CoV-2 susceptibility in the Swiss HIV Cohort Study.

BACKGROUND: Factors influencing susceptibility to SARS-CoV-2 remain to be resolved. Using data of the Swiss HIV Cohort Study (SHCS) on 6,270 people with HIV (PWH) and serologic assessment for SARS-CoV-2 and circulating-human-coronavirus (HCoV) antibodies, we investigated the association of HIV-related and general parameters with SARS-CoV-2 infection. METHODS: We analyzed SARS-CoV-2 PCR-tests, COVID-19 related hospitalizations, and deaths reported to the SHCS between January 1, 2020 and December 31, 2021. Antibodies to SARS-CoV-2 and HCoVs were determined in pre-pandemic (2019) and pandemic (2020) bio-banked plasma and compared to HIV-negative individuals. We applied logistic regression, conditional logistic regression, and Bayesian multivariate regression to identify determinants of SARS-CoV-2 infection and Ab responses to SARS-CoV-2 in PWH. RESULTS: No HIV-1-related factors were associated with SARS-CoV-2 acquisition. High pre-pandemic HCoV antibodies were associated with a lower risk of subsequent SARS-CoV-2 infection and with higher SARS-CoV-2 antibody responses upon infection. We observed a robust protective effect of smoking on SARS-CoV-2-infection risk (aOR= 0.46 [0.38,0.56], p=2.6*10-14), which occurred even in previous smokers, and was highest for heavy smokers. CONCLUSIONS: Our findings of two independent protective factors, smoking and HCoV antibodies, both affecting the respiratory environment, underscore the importance of the local immune milieu in regulating susceptibility to SARS-CoV-2.

Prior infections and effectiveness of SARS-CoV-2 vaccine in test-negative studies: A systematic review and meta-analysis.

Prior infection with SARS-CoV-2 can provide protection against infection and severe COVID-19. We aimed to determine the impact of pre-existing immunity on the vaccine effectiveness (VE) estimates. We systematically reviewed and meta-analysed 66 test-negative design (TND) studies that examined VE against infection or severe disease (hospitalization, ICU admission, or death) for primary vaccination series. Pooled VE among studies that included people with prior COVID-19 infection was lower against infection (pooled VE: 77%; 95% confidence interval (CI): 72%, 81%) and severe disease (pooled VE: 86%; 95% CI: 83%, 89%), compared with studies that excluded people with prior COVID-19 infection (pooled VE against infection: 87%; 95% CI: 85%, 89%; pooled VE against severe disease: 93%; 95% CI: 91%, 95%). There was a negative correlation between VE estimates against infection and severe disease, and the cumulative incidence of cases before the start of the study or incidence rates during the study period. We found clear empirical evidence that higher levels of pre-existing immunity were associated with lower VE estimates. Prior infections should be treated as both a confounder and effect modificatory when the policies target the whole population or stratified by infection history, respectively.

Adjuvant-free parenterally injectable vaccine platform that harnesses previously induced IgG as an antigen delivery carrier.

Subunit vaccines are among the most useful vaccine modalities; however, their low immunogenicity necessitates the addition of adjuvants. Although adjuvants improve immune responses induced by vaccines, they often cause adverse reactions. To address this, we developed an adjuvant-free subunit vaccine platform that uses pre-existing antibodies generated from past infections or vaccinations as carriers for the delivery of vaccine antigens. Although we have confirmed the usefulness of this platform for nasal vaccines, its suitability as a parenterally injectable vaccine remains uncertain. Here, we verified the potential of our vaccine platform to harness pre-existing immunity for parenterally injectable vaccines. We generated RBD-HA by combining the receptor binding domain (RBD) derived from SARS-CoV-2 as a vaccine antigen with hemagglutinin (HA) sourced from influenza viruses to serve as the carrier protein. We revealed that subcutaneous vaccination with RBD-HA effectively triggered strong RBD-specific IgG responses in mice previously infected with the influenza A virus, even in the absence of adjuvants, and conferred protection to mice against SARS-CoV-2 upon challenge. Furthermore, we revealed that vaccination with RBD-HA did not induce an inflammatory response, such as inflammatory cytokine production, swelling, and recruitment of inflammatory immune cells, whereas conventional vaccines combined with adjuvants induced these adverse reactions. In addition, we demonstrated the remarkable versatility of this platform using a vaccine antigen derived from Streptococcus pneumoniae. These findings indicate the potential of this adjuvant-free vaccine platform to enhance the efficacy of parenterally injectable subunit vaccines and reduce adverse reactions.

Pre-existing immunity to SARS-CoV-2 associates with strong T cell responses induced by inactivated COVID-19 vaccines.

Individuals with a recent common cold coronavirus infection, which leads to pre-existing immunity against SARS-CoV-2, displayed a less severe course of COVID-19. However, the relationship between pre-existing immunity against SARS-CoV-2 and the inactivated-vaccine-induced immune response is still unknown. Here, 31 healthcare workers who received standard two doses of inactivated COVID-19 vaccines (Weeks 0 and 4, respectively) were enrolled, vaccine-induced neutralization and T cell responses were detected, and the correlation between the pre-existing SARS-CoV-2-specific immunity was analyzed. We found the SARS-CoV-2-specific antibodies, pseudovirus neutralization test (pVNT) titers, and spike-specific interferon gamma (IFN-γ) production in CD4+ and CD8+ T cells were significantly elevated after two doses of inactivated vaccines. Interestingly, the pVNT titers after the second dose of vaccination displayed no significant correlation with the pre-existing SARS-CoV-2-specific antibodies or B cells, nor the pre-existing spike-specific CD4+ T cells. Notably, the spike-specific T cell response after the second dose of vaccination was positively correlated with the pre-existing receptor binding domain (RBD)-specific B cells and CD4+ T cells, which were documented by the frequencies of RBD-binding B cells, the breadth of RBD-specific B cell epitopes, and the frequency of IFN-γ-expressing RBD-specific CD4+ T cells. Overall, the inactivated-vaccine-induced T cell responses, not the inactivated-vaccine-induced neutralization, closely correlated with pre-existing immunity to SARS-CoV-2. Our results provide a better understanding of inactivated-vaccine-induced immunity and help predict the immunogenicity induced by inactivated vaccines in individuals.

Does pre-existing immunity determine the course of SARS-CoV-2 infection in health-care workers? Single-center experience.

OBJECTIVES: To assess the severity of symptoms, duration of infection and viral loads of health-care workers (HCWs) who tested positive for Coronavirus disease 2019 (COVID-19) during Omicron's prevalence, in regard to vaccination and previous infection. METHODS: During 2 weeks of highest rate of COVID-19 cases in Bosnia and Herzegovina, the positive nasopharyngeal swabs were analysed in 141 HCWs by reverse transcription quantitative PCR, targeting four different genes: RdRp, E, N and nsp14. Uniformed questionnaire was used to collect relevant sociodemographic and epidemiological data from HCWs divided into four groups: unvaccinated/not previously infected (group 1); unvaccinated/previously infected (group 2); vaccinated/not previously infected (group 3); and vaccinated/previously infected (group 4). RESULTS: We observed that occurrence of fever and smell or taste loss were more frequent in group 1 (86.4% and 25%) and group 3 (76.9% and 19.2%), in comparison to group 2 (64.4% and 6.7%) and group 4 (69.2% and 3.8%), (p = 0.023 and p = 0.003). Although statistically not significant, group 2 (61.9%), group 3 (65.4%), and group 4 (70.8%) experienced negativization within 7 days of positive RT-qPCR test, whereas 51.2% of HCWs from group 1 tested negative later on. There is no significant difference between all four groups regarding Ct values of analysed genes. CONCLUSION: During Omicron's prevalence, the vaccination had less substantial effect on symptomatic disease among HCWs, while fever and loss of smell or taste were considerably less likely to occur upon reinfection. Since viral loads and negativization periods do not seem to significantly vary, irrespective of pre-existing immunity, systemic vaccination and mask-wearing should still be considered among HCWs.

AAV-CRISPR Gene Editing Is Negated by Pre-existing Immunity to Cas9.

Adeno-associated viral (AAV) vectors are a leading candidate for the delivery of CRISPR-Cas9 for therapeutic genome editing in vivo. However, AAV-based delivery involves persistent expression of the Cas9 nuclease, a bacterial protein. Recent studies indicate a high prevalence of neutralizing antibodies and T cells specific to the commonly used Cas9 orthologs from Streptococcus pyogenes (SpCas9) and Staphylococcus aureus (SaCas9) in humans. We tested in a mouse model whether pre-existing immunity to SaCas9 would pose a barrier to liver genome editing with AAV packaging CRISPR-Cas9. Although efficient genome editing occurred in mouse liver with pre-existing SaCas9 immunity, this was accompanied by an increased proportion of CD8+ T cells in the liver. This cytotoxic T cell response was characterized by hepatocyte apoptosis, loss of recombinant AAV genomes, and complete elimination of genome-edited cells, and was followed by compensatory liver regeneration. Our results raise important efficacy and safety concerns for CRISPR-Cas9-based in vivo genome editing in the liver.

Emergence of Novel Coronavirus and COVID-19: whether to stay or die out?

The last century has witnessed several assaults from RNA viruses, resulting in millions of death throughout the world. The 21st century appears no longer an exception, with the trend continued with escalated fear of SARS coronavirus in 2002 and further concern of influenza H5N1 in 2003. A novel influenza virus created the first pandemic of the 21st century, the pandemic flu in 2009 preceded with the emergence of another deadly virus, MERS-CoV in 2012. A novel coronavirus "SARS-CoV-2" (and the disease COVID-19) emerged suddenly, causing a rapid outbreak with a moderate case fatality rate. This virus is continuing to cause health care providers grave concern due to the lack of any existing immunity in the human population, indicating their novelty and lack of previous exposure. The big question is whether this novel virus will be establishing itself in an endemic form or will it eventually die out? Endemic viruses during circulation may acquire mutations to infect naïve, as well as individual with pre-existing immunity. Continuous monitoring is strongly advisable, not only to the newly infected individuals, but also to those recovered individuals who were infected by SARS-CoV-2 as re-infection may lead to the selection of escape mutants and subsequent dissemination to the population.

Targeting a Pre-existing Anti-transgene T Cell Response for Effective Gene Therapy of MPS-I in the Mouse Model of the Disease.

Mucopolysaccharidosis type I (MPS-I) is a severe genetic disease caused by a deficiency of the alpha-L-iduronidase (IDUA) enzyme. Ex vivo hematopoietic stem cell (HSC) gene therapy is a promising therapeutic approach for MPS-I, as demonstrated by preclinical studies performed in naive MPS-I mice. However, after enzyme replacement therapy (ERT), several MPS-I patients develop anti-IDUA immunity that may jeopardize ex vivo gene therapy efficacy. Here we treat MPS-I mice with an artificial immunization protocol to mimic the ERT effect in patients, and we demonstrate that IDUA-corrected HSC engraftment is impaired in pre-immunized animals by IDUA-specific CD8+ T cells spared by pre-transplant irradiation. Conversely, humoral anti-IDUA immunity does not impact on IDUA-corrected HSC engraftment. The inclusion of lympho-depleting agents in pre-transplant conditioning of pre-immunized hosts allowes rescue of IDUA-corrected HSC engraftment, which is proportional to CD8+ T cell eradication. Overall, these data demonstrate the relevance of pre-existing anti-transgene T cell immunity on ex vivo HSC gene therapy, and they suggest the application of tailored immune-depleting treatments, as well as a deeper immunological characterization of patients, to safeguard the therapeutic effects of ex vivo HSC gene therapy in immunocompetent hosts.

Pre-existing Immunity to Oncolytic Virus Potentiates Its Immunotherapeutic Efficacy.

Anti-viral immunity presents a major hurdle for systemically administered oncolytic viruses (OV). Intratumoral OV therapy has a potential to overcome this problem through activation of anti-tumor immune response, with local and abscopal effects. However, the effects of anti-viral immunity in such a setting are still not well defined. Using Newcastle Disease Virus (NDV) as a model, we explore the effects of pre-existing anti-viral immunity on therapeutic efficacy in syngeneic mouse tumor models. Unexpectedly, we find that while pre-existing immunity to NDV limits its replication in tumors, tumor clearance, abscopal anti-tumor immune effects, and survival are not compromised and, on the contrary, are superior in NDV-immunized mice. These findings demonstrate that pre-existing immunity to NDV may increase its therapeutic efficacy through potentiation of systemic anti-tumor immunity, which provides clinical rationale for repeated therapeutic dosing and prompts investigation of such effects with other OVs.

Bolstering Components of the Immune Response Compromised by Prior Exposure to Adenovirus: Guided Formulation Development for a Nasal Ebola Vaccine.

The severity and longevity of the current Ebola outbreak highlight the need for a fast-acting yet long-lasting vaccine for at-risk populations (medical personnel and rural villagers) where repeated prime-boost regimens are not feasible. While recombinant adenovirus (rAd)-based vaccines have conferred full protection against multiple strains of Ebola after a single immunization, their efficacy is impaired by pre-existing immunity (PEI) to adenovirus. To address this important issue, a panel of formulations was evaluated by an in vitro assay for their ability to protect rAd from neutralization. An amphiphilic polymer (F16, FW ∼39,000) significantly improved transgene expression in the presence of anti-Ad neutralizing antibodies (NAB) at concentrations of 5 times the 50% neutralizing dose (ND50). In vivo performance of rAd in F16 was compared with unformulated virus, virus modified with poly(ethylene) glycol (PEG), and virus incorporated into poly(lactic-co-glycolic) acid (PLGA) polymeric beads. Histochemical analysis of lung tissue revealed that F16 promoted strong levels of transgene expression in naive mice and those that were exposed to adenovirus in the nasal cavity 28 days prior to immunization. Multiparameter flow cytometry revealed that F16 induced significantly more polyfunctional antigen-specific CD8+ T cells simultaneously producing IFN-γ, IL-2, and TNF-α than other test formulations. These effects were not compromised by PEI. Data from formulations that provided partial protection from challenge consistently identified specific immunological requirements necessary for protection. This approach may be useful for development of formulations for other vaccine platforms that also employ ubiquitous pathogens as carriers like the influenza virus.

Role of pre-existing immunity in driving the dengue virus serotype 2 genotype shift in the Philippines: A retrospective analysis of serological data.

OBJECTIVE: The invasion of dengue virus (DENV)-2 Cosmopolitan genotype into the Philippines, where the Asian II genotype previously circulated challenges the principle of dengue serotype-specific immunity. Assessment of antibodies in this population may provide a mechanistic basis for how new genotypes emerge in dengue-endemic areas. METHODS: We evaluated the neutralizing antibody (nAb) and antibody-dependent enhancement (ADE) responses against the two genotypes using archived serum samples collected from 333 patients with confirmed dengue in Metro Manila, Philippines, before, during, and after the introduction of the Cosmopolitan genotype. We quantified nAb titers in baby hamster kidney (BHK-21) cells with or without the Fcγ receptor IIA (FcγRIIA) to detect the capacity of virus-antibody complexes to neutralize or enhance DENV. RESULTS: The nAb potency of the archived serum samples against the two genotypes was greatly affected by the presence of FcγRIIA. We found significant differences in nAb titers between the two genotypes in BHK-21 cells with FcγRIIA (P <0.0001). The archived serum samples were incapable of fully neutralizing the Cosmopolitan genotype, but instead strongly promoted its ADE compared to the Asian II genotype (P <0.0001). CONCLUSION: These results reinforce the role of pre-existing immunity in driving genotype shifts. Our finding that specific genotypes exhibit differing susceptibilities to ADE by cross-reactive antibodies may have implications for dengue vaccine development.

Pre-Existing Immunity Predicts Response to First-Line Immunotherapy in Non-Small Cell Lung Cancer Patients.

T-cell-mediated anti-tumoral responses may have significant clinical relevance as a biomarker for response to immunotherapy. The value of peripheral blood pre-existing tumor antigen-specific T cells (PreI+) as a predictive immunotherapy biomarker in NSCLC patients was investigated, along with the frequency of various circulating immune cells. Fifty-two treatment-naïve, stage III/IV NSCLC patients, treated with front-line immune checkpoint inhibitors (ICI)-containing regimens were enrolled. PreI was calculated as the percentages of CD3+IFNγ+ cells after in vitro co-cultures of PBMCs with peptides against four different Tumor-Associated Antigens (TAA). Immunophenotyping of peripheral blood immune cells was performed using multicolor flow cytometry. PreI+ T cells were detected in 44% of patients. Median overall survival (OS) was significantly higher in PreI+ patients compared to PreI- patients (not reached vs. 321 days, respectively; p = 0.014). PreI+ patients had significantly higher numbers of possible exhausted CD3+CD8+PD-1+ cells and lower percentages of immunosuppressive Tregs compared to PreI- patients. Additionally, patients with PreI+ and low numbers of peripheral blood M-MDSCs had a significant survival advantage compared to the rest of the patients. Thus, combining pre-existing tumor antigen-specific immunity before initiation of ICI in NSCLC patients with selected immune-suppressive cells could identify patients who have a favorable clinical outcome when treated with ICI-containing regimens.

Impact of pre-existing cross-reactive antibodies on cyclic dengue outbreaks in the hyperendemic region of Bali, Indonesia.

The four serotypes of the dengue virus (DENV) cause a range of diseases ranging from mild fever to severe conditions. Understanding the immunological interactions among the four serotypes is crucial in comprehending the dynamics of serotype shifting during outbreaks in areas where all four serotypes co-circulate. Hence, we evaluated the neutralizing antibody and antibody-dependent enhancement responses against the four DENV serotypes using acute-phase plasma samples collected from 48 laboratory-confirmed dengue patients during a dengue outbreak in Bali, Indonesia in 2022. Employing single-round infectious particles to exclusively investigate immunogenicity to the structural surface proteins of DENV, which are the targets of antibodies, we found that individuals with a probable prior history of DENV-1 infection exhibited increased susceptibility to secondary DENV-3 infection, attributed to cross-reactive antibodies with limited neutralizing activity against DENV-3 (geometric mean 50 % neutralization titer (GMNT50) = 47.6 ± 11.5). This susceptibility was evident in vitro, with a mean fold enhancement of 28.4 ± 33.9. Neutralization titers against DENV-3 were significantly lower compared to other serotypes (DENV-1 GMNT50 = 678.1 ± 9.0; DENV-2 GMNT50 = 210.5 ± 8.7; DENV-4 GMNT50 = 95.14 ± 7.0). We demonstrate that prior immunity to one serotype provides limited cross-protection against the other serotypes, influencing the dominant serotype in subsequent outbreaks. These findings underscore the complexity of dengue immunity and its implications for vaccine design and transmission dynamics in hyperendemic regions.

Cross-protective efficacy and safety of an adenovirus-based universal influenza vaccine expressing nucleoprotein, hemagglutinin, and the ectodomain of matrix protein 2.

It is necessary to develop universal vaccines that act broadly and continuously to combat regular seasonal epidemics of influenza and rare pandemics. The aim of this study was to find the optimal dose regimen for the efficacy and safety of a mixture of previously developed recombinant adenovirus-based vaccines that expressed influenza nucleoprotein, hemagglutinin, and ectodomain of matrix protein 2 (rAd/NP and rAd/HA-M2e). The vaccine efficacy and safety were measured in the immunized mice with the mixture of rAd/NP and rAd/HA-M2e intranasally or intramuscularly. The minimum dose that would be efficacious in a single intranasal administration of the vaccine mixture and cross-protective efficacy against various influenza strains were examined. In addition, the immune responses that may affect the cross-protective efficacy were measured. We found that intranasal administration is an optimal route for 107 pfu of vaccine mixture, which is effective against pre-existing immunity against adenovirus. In a study to find the minimum dose with vaccine efficacy, the 106 pfu of vaccine mixture showed higher antibody titers to the nucleoprotein than did the same dose of rAd/NP alone in the serum of immunized mice. The 106 pfu of vaccine mixture overcame the morbidity and mortality of mice against the lethal dose of pH1N1, H3N2, and H5N1 influenza infections. No noticeable side effects were observed in single and repeated toxicity studies. We found that the mucosal administration of adenovirus-based universal influenza vaccine has both efficacy and safety, and can provide cross-protection against various influenza infections even at doses lower than those previously known to be effective.

Pre-existing immunity to influenza aids ferrets in developing stronger and broader H3 vaccine-induced antibody responses.

Influenza seasons occur annually, building immune history for individuals, but the influence of this history on subsequent influenza vaccine protection remains unclear. We extracted data from an animal trial to study its potential impact. The trial involved 80 ferrets, each receiving either one type of infection or a placebo before vaccination. We quantified the vaccine protection by evaluating hemagglutination inhibition (HAI) antibody titer responses. We tested whether hosts with different infection histories exhibited similar level of responses when receiving the same vaccine for all homologous and heterologous outcomes. We observed that different pre-existing immunities were generally beneficial to vaccine induced responses, but varied in magnitude. Without pre-immunity, post-vaccination HAI titers after the 1st dose of the vaccine were less likely to be above 1:40, and a booster shot was needed. Our study suggests that pre-existing immunity may strengthen and extend the homologous and heterologous vaccine responses.

Long-lasting humoral and cellular memory immunity to vaccinia virus Tiantan provides pre-existing immunity against mpox virus in Chinese population.

Investigating immune memory to vaccinia virus and pre-existing immunity to mpox virus (MPXV) among the population is crucial for the global response to this ongoing mpox epidemic. Blood was sampled from vaccinees inoculated with vaccinia virus Tiantan (VTT) strain born before 1981 and unvaccinated control subjects born since 1982. After at least 40 years of the inoculation, 60% or 5% VTT vaccinees possess neutralizing antibodies (NAbs) to VTT or MPXV, with at least 50% having T cell memory to VTT protein antigens. Notably, 46.7% vaccinees show pre-existing T cell responses to MPXV. Broad pre-existing CD8+ T cell reactivities to MPXV are detected not only against conserved epitopes but also against variant epitopes between VTT and MPXV. Persistent NAbs and T cell memory to VTT among vaccinees, along with pre-existing T cells to MPXV among both vaccinees and the unvaccinated population, indicate a particular immune barrier to mpox.

Effects of pre-existing anti-carrier immunity and antigenic element multiplicity on efficacy of a modular virus-like particle vaccine.

Modularization of a peptide antigen for presentation on a microbially synthesized murine polyomavirus (MuPyV) virus-like particle (VLP) offers a new alternative for rapid and low-cost vaccine delivery at a global scale. In this approach, heterologous modules containing peptide antigenic elements are fused to and displayed on the VLP carrier, allowing enhancement of peptide immunogenicity via ordered and densely repeated presentation of the modules. This study addresses two key engineering questions pertaining to this platform, exploring the effects of (i) pre-existing carrier-specific immunity on modular VLP vaccine effectiveness and (ii) increase in the antigenic element number per VLP on peptide-specific immune response. These effects were studied in a mouse model and with modular MuPyV VLPs presenting a group A streptococcus (GAS) peptide antigen, J8i. The data presented here demonstrate that immunization with a modular VLP could induce high levels of J8i-specific antibodies despite a strong pre-existing anti-carrier immune response. Doubling of the J8i antigenic element number per VLP did not enhance J8i immunogenicity at a constant peptide dose. However, the strategy, when used in conjunction with increased VLP dose, could effectively increase the peptide dose up to 10-fold, leading to a significantly higher J8i-specific antibody titer. This study further supports feasibility of the MuPyV modular VLP vaccine platform by showing that, in the absence of adjuvant, modularized GAS antigenic peptide at a dose as low as 150 ng was sufficient to raise a high level of peptide-specific IgGs indicative of bactericidal activity.

Impact of prior flavivirus vaccination on immunogenicity and efficacy of an inactivated Zika vaccine in Indian rhesus macaques.

Flaviviruses are antigenically related. We evaluated the immunogenicity and efficacy of Takeda's purified inactivated Zika vaccine (PIZV) candidate in macaques previously vaccinated with several commercially available heterologous flavivirus vaccines. Heterologous flavivirus vaccination did not elicit Zika virus (ZIKV) neutralizing antibodies and did not impact neutralizing antibody titers after one dose of PIZV. After a second PIZV dose previous vaccination with flavivirus vaccines had variable impact on ZIKV neutralizing antibody titers. However, all macaques were protected against viremia after Zika virus challenge 8-12 months post-PIZV vaccination. Therefore, vaccine-induced immunity against heterologous flavivirus vaccines does not impact PIZV efficacy in macaques.