Pre-existing immunity to cytomegalovirus in macaques influences human CMV vaccine responses in preclinical models

Development of a human cytomegalovirus (HCMV) vaccine is a Tier 1 priority by the National Institutes of Medicine, as HCMV is the most common congenital infection globally and most frequent infectious complication in transplant patients. Relevant preclinical non-human primate models used for testing HCMV vaccine immunogenicity are rhesus and cynomolgous monkeys. However, a complication in using these models is that species-specific CMV variants are endemic in non-human primate breeding colonies. We hypothesize that natural immunity to species-specific CMV in rhesus and cynomolgous monkeys impacts HCMV vaccine immunogenicity and may interfere with our ability to fully interpret vaccine immunogenicity. A modified mRNA vaccine encoding HCMV glycoprotein (gB) and the pentameric complex (PC) packaged in lipid nanoparticles (LNP) was delivered intramuscularly to groups of cynomolgous (n = 16, CyCMV-seropositive) and rhesus macaques (n = 24, RhCMV-seropositive). High pre-vaccination IgG binding responses to HCMV gB were present in both species, but pre-vaccination binding responses to PC were mostly present in rhesus macaques. Yet, at least a log increase in both PC and gB-specific plasma IgG levels was detected post-second HCMV mRNA vaccination in both species. Both species responded with high epithelial cell neutralizing antibody responses at 4 weeks post second HCMV mRNA vaccination, but limited fibroblast neutralizing antibodies. HCMV gB + PC mRNA/LNP vaccine also elicited IgG binding responses to cell-associated gB, an identified immune correlate of protection, in both species after the second vaccination, and there was a moderately strong direct correlation between this pre- and post-vaccination response in rhesus macaques. Based on the correlation between pre-existing and post-vaccine gB-specific binding responses in rhesus macaques, we conclude that species-specific CMV variant-specific antibody responses contribute to antibody responses to HCMV vaccination in primate models, indicating that pre-existing immunity must be taken into account in non-human primate preclinical models and will impact immunogenicity of HCMV vaccines seropositive human vaccinees.     

Human cytomegalovirus gH/gL/UL128/UL130/UL131A complex elicits potently neutralizing antibodies in mice

Human cytomegalovirus (HCMV) is a member of the β-herpesvirus family that causes significant disease worldwide. Although evidence exists that neutralizing antibodies and cytotoxic T cell responses to HCMV antigens can prevent HCMV disease and/or infection, there are no approved vaccines to prevent HCMV disease. Over the past 10 years, multiple HCMV vaccines have been tested in man but only partial protection has been achieved in these studies. HCMV contains multiple surface-expressed glycoproteins that are critical to viral entry, including gB, the gM/gN complex, the gH/gL complex, and a pentameric gH/gL/UL128/UL130/UL131A complex. Recently we showed that viral replicon particles (VRPs) expressing the gH/gL complex elicited more potently neutralizing antibodies than VRPs expressing gB in mice. Here we compare the immunogenicity of VRPs encoding the HCMV gH/gL and pentameric complexes, as well as purified gH/gL and pentameric complexes administered in the presence or absence of the MF59 adjuvant. The results of these studies indicate that the pentameric complex elicits significantly higher levels of neutralizing antibodies than the gH/gL complex, and that MF59 significantly increases the potency of each complex. In addition, we show that animals immunized with pentamer encoding VRPs or the pentameric subunit produce antibodies that recognize a broad range of antigenic sites on the complex. Taken together, these studies support the utility of the pentameric complex in HCMV vaccine candidates.     

Characterization of humoral and cell-mediated immunity induced by mRNA vaccines expressing influenza hemagglutinin stem and nucleoprotein in mice and nonhuman primates

In response to immune pressure, influenza viruses evolve, producing drifted variants capable of escaping immune recognition. One strategy for inducing a broad-spectrum immune response capable of recognizing multiple antigenically diverse strains is to target conserved proteins or protein domains. To that end, we assessed the efficacy and immunogenicity of mRNA vaccines encoding either the conserved stem domain of a group 1 hemagglutinin (HA), a group 2 nucleoprotein (NP), or a combination of the two antigens in mice, as well as evaluated immunogenicity in naïve and influenza seropositive nonhuman primates (NHPs). HA stem-immunized animals developed a robust anti-stem antibody binding titer, and serum antibodies recognized antigenically distinct group 1 HA proteins. These antibodies showed little to no neutralizing activity in vitro but were active in an assay measuring induction of antibody-dependent cellular cytotoxicity. HA-directed cell-mediated immunity was weak following HA stem mRNA vaccination; however, robust CD4 and CD8 T cell responses were detected in both mice and NHPs after immunization with mRNA vaccines encoding NP. Both HA stem and NP mRNA vaccines partially protected mice from morbidity following lethal influenza virus challenge, and superior efficacy against two different H1N1 strains was observed when the antigens were combined. In vivo T cell depletion suggested that anti-NP cell-mediated immunity contributed to protection in the mouse model. Taken together, these data show that mRNA vaccines encoding conserved influenza antigens, like HA stem and NP in combination, induce broadly reactive humoral responses as well as cell-mediated immunity in mice and NHPs, providing protection against homologous and heterologous influenza infection in mice.     

Self-adjuvanted mRNA vaccines induce local innate immune responses that lead to a potent and boostable adaptive immunity

mRNA represents a new platform for the development of therapeutic and prophylactic vaccines with high flexibility with respect to production and application. We have previously shown that our two component self-adjuvanted mRNA-based vaccines (termed RNActive® vaccines) induce balanced immune responses comprising both humoral and cellular effector as well as memory responses. Here, we evaluated the early events upon intradermal application to gain more detailed insights into the underlying mode of action of our mRNA-based vaccine.We showed that the vaccine is taken up in the skin by both non-leukocytic and leukocytic cells, the latter being mostly represented by antigen presenting cells (APCs). mRNA was then transported to the draining lymph nodes (dLNs) by migratory dendritic cells. Moreover, the encoded protein was expressed and efficiently presented by APCs within the dLNs as shown by T cell proliferation and immune cell activation, followed by the induction of the adaptive immunity. Importantly, the immunostimulation was limited to the injection site and lymphoid organs as no proinflammatory cytokines were detected in the sera of the immunized mice indicating a favorable safety profile of the mRNA-based vaccines. Notably, a substantial boostability of the immune responses was observed, indicating that mRNA can be used effectively in repetitive immunization schedules. The evaluation of the immunostimulation following prime and boost vaccination revealed no signs of exhaustion as demonstrated by comparable levels of cytokine production at the injection site and immune cell activation within dLNs.In summary, our data provide mechanistic insight into the mode of action and a rational for the use of mRNA-based vaccines as a promising immunization platform.     

Use of flow cytometry for characterization of human cytomegalovirus vaccine particles

Despite a 40-year effort, an effective vaccine against human cytomegalovirus (HCMV) remains an unmet medical need. The discovery of potent neutralizing epitopes on the pentameric gH complex (gH/gL/UL128/130/131) has reenergized HCMV vaccine development. Our whole-virus vaccine candidate, currently in a Phase I clinical trial, is based on the attenuated AD169 strain with restored expression of the pentameric gH complex. Given the complexity of a whole-virus vaccine, improved analytical methods have been developed to better characterize heterogeneous viral particles released from infected cells during vaccine production. Here we show the utility of a commercial flow cytometer for the detection of individual HCMV particles, either via light scattering or using fluorescence after labeling of specific antigens. Rapid measurements requiring minimal material provide near real-time information on particle concentration, distributions of different particle types, and product purity. Additionally, utilizing immunoreagents has allowed us to characterize the distribution of key antigens across individual particles and particle types.     

Adjuvant formulation for use in vaccines to elicit both cell-mediated and humoral immunity

Adjuvant formulations which elicit both humoral and cell-mediated immunity will be required for vaccines based on peptides, viral and bacterial subunits and genetically engineered antigens. This report describes an adjuvant formulation which increases both cell-mediated and humoral immunity and is free of significant side effects encountered with other adjuvants or vehicles. The components include the threonyl analogue of muramyl dipeptide, Tween 80, Pluronic L121 and squalane. This formulation was found to be effective with several antigens, in several species, including rodents, cats and monkeys. These results suggest that the formulation will be useful for both human and veterinary vaccines.     

The next generation recombinant human cytomegalovirus vaccine candidates—Beyond gB

Human cytomegalovirus (HCMV) infects the majority of the global population and persists within the infected host for life; infection of healthy adults rarely leads to severe acute clinical symptoms. In contrast, HCMV is a leading infectious cause of congenital disease and a common cause of complications in transplant recipients. A vaccine to prevent HCMV disease in these populations is a widely recognized medical need. We review recent advances in our understanding of the candidate vaccine antigens and published clinical trial data for the four most recent HCMV vaccine candidates: a gB subunit adjuvanted with MF59, a DNA vaccine expressing gB and pp65, alphavirus replicon particles (VRPs) expressing gB and a pp65–IE1 fusion protein, and a pp65 peptide vaccine. The candidates are safe, although some adverse events were reported for an adjuvanted variant of the pp65 peptide vaccine. The gB/MF59 vaccine elicited strong humoral responses with limited durability. The gB/pp65 DNA vaccine elicited cellular immunity, and the pp65 peptide vaccine elicited modest cellular immunity, but only when formulated with an adjuvant. Only the VRP vaccine expressing gB and pp65–IE1 elicited both humoral and cellular immunity. The gB/MF59 vaccine showed a short-term 50% efficacy at preventing infection of seronegative women and significantly reduced viremia and need for antivirals in solid organ transplant recipients, and the gB/pp65 DNA vaccine showed signs of clinical benefit in hematopoietic stem cell transplant recipients. Importantly, the partial efficacy of the subunit and DNA vaccines is new evidence that both humoral and cellular immunity contribute to controlling HCMV-related disease. These data show the clinical feasibility of a recombinant HCMV vaccine. We discuss areas for potential improvements in the next generation of vaccine candidates.     

Engineering immunity for next generation HIV vaccines: The intersection of bioengineering and immunology

Bioengineering approaches grounded in immunology have the potential for the discovery and development of a successful HIV vaccine. The overarching goal is to engineer immunity through a fusion of immunology with bioengineering to create novel strategies for the design, development and delivery of vaccines based on the controlled modulation of the immune system. To foster these collaborations, the National Institute of Allergy and Infectious Diseases (NIAID) and National Institute of Biomedical Imaging and Bioengineering (NIBIB) brought together a group of experts (see Table 1) from these diverse fields for a workshop in September 2018 to: (1) engage the engineering, immunology, and HIV vaccinology communities to dialogue on the topic of an HIV vaccine and; (2) generate a framework of new and innovative research avenues to explore in HIV vaccinology between knowledge stakeholders and problem solvers.     

Induced humoral immunity of different types of vaccines against most common variants of SARS-CoV-2 in Egypt prior to Omicron outbreak

The diversity of SARS-CoV-2 continues to lead to the emergence of new SARS-CoV-2 variants. SARS-CoV-2 antibody assays are crucial in managing the COVID-19 pandemic by determining the neutralizing antibody response. This study aims to investigate vaccine-induced antibodies against most common variants of SARS-CoV-2 in Egypt. Sera samples were collected from vaccinated participants and neutralizing activity against the SARS-CoV-2 variants was determined using microneutralization assay. Our results show that the BNT162b2 (Pfizer-BioNTech), ChAdOx1 nCov-19 (AstraZeneca), and Ad26.COV2.S COVID-19 (Janssen) vaccines elicited neutralizing antibody responses more than the BBIBP-CorV vaccine (Sinopharm) against B.1, C.36.3, and AY.32 (Delta) variants. While vaccines remain highly effective in managing the COVID-19 pandemic, ongoing monitoring of vaccine effectiveness is needed.     

A cytomegalovirus DNA vaccine induces antibodies that block viral entry into fibroblasts and epithelial cells

A vaccine to prevent congenital cytomegalovirus (CMV) infections is a national priority. Investigational vaccines have targeted the viral glycoprotein B (gB) as an inducer of neutralizing antibodies and phosphoprotein 65 (pp65) as an inducer of cytotoxic T cells. Antibodies to gB neutralize CMV entry into all cell types but their potency is low compared to antibodies that block epithelial cell entry through targeting the pentameric complex (gH/gL/UL128/UL130/UL131). Hence, more potent overall neutralizing responses may result from a vaccine that combines gB with pentameric complex-derived antigens. To assess the ability of pentameric complex subunits to generate epithelial entry neutralizing antibodies, DNA vaccines encoding UL128, UL130, and/or UL131 were formulated with Vaxfectin^®, an adjuvant that enhances antibody responses to DNA vaccines. Mice were immunized with individual DNA vaccines or with pair-wise or trivalent combinations. Only the UL130 vaccine induced epithelial entry neutralizing antibodies and no synergy was observed from bi- or trivalent combinations. In rabbits the UL130 vaccine again induced epithelial entry neutralizing antibodies while UL128 or UL131 vaccines did not. To evaluate compatibility of the UL130 vaccine with DNA vaccines encoding gB or pp65, mono-, bi-, or trivalent combinations were evaluated. Fibroblast and epithelial entry neutralizing titers did not differ between rabbits immunized with gB alone vs. gB/UL130, gB/pp65, or gB/UL130/pp65 combinations, indicating a lack of antagonism from coadministration of DNA vaccines. Importantly, gB-induced epithelial entry neutralizing titers were substantially higher than activities induced by UL130, and both fibroblast and epithelial entry neutralizing titers induced by gB alone as well as gB/pp65 or gB/UL130/pp65 combinations were comparable to those observed in sera from humans with naturally-acquired CMV infections. These findings support further development of Vaxfectin^®-formulated gB-expressing DNA vaccine for prevention of congenital CMV infections.     

Restoration of viral epithelial tropism improves immunogenicity in rabbits and rhesus macaques for a whole virion vaccine of human cytomegalovirus

Maternal immunity to human cytomegalovirus (HCMV) prior to conception is ∼70% protective against congenital transmission and in utero infection of HCMV. Both functional antibodies capable of neutralizing virus and effective T-cells are believed to be important for the protection. Previous HCMV vaccines have rarely been shown able to induce neutralizing antibody titers comparable to those seen in naturally infected HCMV seropositive subjects. Recent studies link a glycoprotein H (gH) complex to receptor-mediated viral entry of endothelial/epithelial cells and leukocytes. This pentameric gH complex, composed of five proteins (gH, gL, UL128, UL130 and UL131 proteins), is notably missing in all HCMV vaccine previously evaluated in clinic. Here we showed that a HCMV virus, with restored expression of the pentameric gH complex, can induce 10-fold higher neutralizing antibody titers than an attenuated AD169 virus or a recombinant glycoprotein B vaccine in multiple animal species in which viral replication is not expected. Encouragingly, the peak neutralizing titers post vaccination in rabbits and monkeys were within 2–4-fold of the levels determined in HCMV seropositive subjects. Functional antibodies by vaccination could further be improved when formulated with a novel adjuvant, and the titers of the antiviral antibodies were sustained in rabbits for over a year after vaccination. These results indicate that the pentameric gH complex is associated with greatly improved functional antibodies following vaccination, and support a vaccine concept based on a nonreplicating whole HCMV with the pentameric gH-associated epithelial tropism restored.     

Motif-optimized subtype A HIV envelope-based DNA vaccines rapidly elicit neutralizing antibodies when delivered sequentially

HIV-1 infection results in the development of a diverging quasispecies unique to each infected individual. Envelope (Env)-specific neutralizing antibodies (NAbs) typically develop over months to years after infection and initially are limited to the infecting virus. In some subjects, antibody responses develop that neutralize heterologous isolates (HNAbs), a phenomenon termed broadening of the NAb response. Studies of co-crystalized antibodies and proteins have facilitated the identification of some targets of broadly neutralizing monoclonal antibodies (NmAbs) capable of neutralizing many or most heterologous viruses; however, the ontogeny of these antibodies in vivo remains elusive. We hypothesize that Env protein escape variants stimulate broad NAb development in vivo and could generate such NAbs when used as immunogens. Here we test this hypothesis in rabbits using HIV Env vaccines featuring: (1) use of individual quasispecies env variants derived from an HIV-1 subtype A-infected subject exhibiting high levels of NAbs within the first year of infection that increased and broadened with time; (2) motif optimization of envs to enhance in vivo expression of DNA formulated as vaccines; and (3) a combined DNA plus protein boosting regimen. Vaccines consisted of multiple env variants delivered sequentially and a simpler regimen that utilized only the least and most divergent clones. The simpler regimen was as effective as the more complex approach in generating modest HNAbs and was more efficient when modified, motif-optimized DNA was used in combination with trimeric gp140 protein. This is a rationally designed strategy that facilitates future vaccine design by addressing the difficult problem of generating HNAbs to HIV by empirically testing the immunogenicity of naturally occurring quasispecies env variants.     

Neutralizing antibody responses in healthcare personnel after three doses of mRNA BNT162b2 vaccine and association with baseline characteristics and past SARS-CoV-2 infection

AimTo estimate neutralizing antibody (NAb) immunity against SARS-CoV-2 in 739 healthcare personnel (HCP) vaccinated with three doses of BNT162b2 mRNA vaccine.MethodsSerum samples were collected at 3, 6, and 9 months after the second vaccine dose and at 7–55 days after the third dose. Samples were tested for NAbs against SARS-CoV-2 receptor binding domain.ResultsThe mean inhibition rates at 3, 6, and 9 months after the second dose were 86.33%, 73.38%, and 61.18%, and increased to 95.57% after the booster dose. Younger HCP and HCP with past SARS-CoV-2 infection had higher inhibition rates while there was an inverse correlation between NAb levels and comorbidities or tobacco use (p-values < 0.001). Increased NAb titers were also noticed in women (p-value = 0.033), especially at the end of the 9-month study period.ConclusionNAb levels increased considerably after a booster mRNA vaccine dose. Host factors and past SARS-CoV-2 infection influence NAb titers.     

Intradermal immunization with inactivated swine influenza virus and adjuvant polydi(sodium carboxylatoethylphenoxy)phosphazene (PCEP) induced humoral and cell-mediated immunity and reduced lung viral titres in pigs

Swine influenza virus is endemic worldwide and it is responsible for significant economic losses to the swine industry. A vaccine that stimulates a rapid and long-lasting protective immune response to prevent this infection is highly sought. Poly[di(sodium carboxylatoethylphenoxy)-phosphazene (PCEP) has demonstrated adjuvant activity when formulated as part of multiple vaccines in mice and pigs. In this study we examined the magnitude and type of immune response induced in pigs vaccinated via the intramuscular or intradermal routes with inactivated swine influenza virus (SIV) H1N1 vaccine formulated with PCEP. Intradermal administration of PCEP-adjuvanted inactivated SIV vaccine stimulated significant anti-SIV antibody titres, increased neutralizing antibodies, and significantly reduced lung virus load with limited reduction of gross lung lesions after challenge with virulent H1N1 relative to control animals. These results indicate that PCEP may be effective as a vaccine adjuvant against swine influenza viruses in pigs and should be considered a potential candidate adjuvant for future swine intradermal influenza vaccines.     

Exploratory study of humoral and cellular immunity to 17DD Yellow Fever vaccination in children and adults residents of areas without circulation of Yellow Fever Virus

The present investigation comprised two independent observational arms to evaluate the influence of pre-existing flavivirus humoral immunity and the age-impact on 17DD-YF vaccination immunity. Flavivirus (YFV; DENV; ZIKV) serology and YF-specific cellular immunity was evaluated in 288 children/9^Mths–4^Yrs and 288 adults/18–49^Yrs residents of areas without YFV circulation. Data demonstrated that flavivirus seropositivity at baseline was higher in Adults as compared to Children (26%;87%;67% vs 6%;13%;15%, respectively). The heterologous flavivirus seropositivity (DENV; ZIKV) did not impact the YF-specific cellular immune response at baseline. However, higher levels of NCD4, EMCD8, IFN-MCD8, NCD19 and nCMCD19 were observed in subjects with pre-existing YFV seropositivity. Primary vaccination of YFV-seronegative volunteers led to higher levels of YF-neutralizing antibodies in Adults as compared to Younger Children (9^Mths–2^Yrs). Although similar seropositivity rates observed amongst Children and Adults at D30-45, lower rates were observed in Younger Children (9^Mths–2^Yrs) at D365 (94%;95%;100% vs 87%;96%;99%, respectively). A progressive decline in antibody levels were reported at D365, being more expressive in Children as compared to Adults. All age-subgroups exhibited at D30-45 increased levels of eEfCD4, EMCD4, IFN-MCD8 and nCMCD19 together with a decrease of eEfCD8 and CMCD8. While an increase of EMCD8 were observed in all subgroups at D30-45, a declined duration at D365 was reported only in Younger Children (9^Mths–2^Yrs). Biomarker signatures further support that only Younger Children (9^Mths–2^Yrs) presented a progressive decline of EMCD8 at D365. Together, these findings demonstrated that regardless the similarities observed in YF-neutralizing antibodies, the age impacts the duration of cellular immune response to primary 17DD-YF vaccination.     

Peptides from cytomegalovirus UL130 and UL131 proteins induce high titer antibodies that block viral entry into mucosal epithelial cells

Cytomegalovirus infections are an important cause of disease for which no licensed vaccine exists. Recent studies have focused on the gH/gL/UL128-131 complex as antibodies to gH/gL/UL128-131 neutralize viral entry into epithelial cells. Prior studies have used cells from the retinal pigment epithelium, while to prevent transmission, vaccine-induced antibodies may need to block viral infection of epithelial cells of the oral or genital mucosa. We found that gH/gL/UL128-131 is necessary for efficient viral entry into epithelial cells derived from oral and genital mucosa, that short peptides from UL130 and UL131 elicit high titer neutralizing antibodies in rabbits, and that such antibodies neutralize viral entry into epithelial cells derived from these relevant tissues. These results suggest that single subunits or peptides may be sufficient to elicit potent epithelial entry neutralizing responses and that secretory antibodies to such neutralizing epitopes have the potential to provide sterilizing immunity by blocking initial mucosal infection.     

Coimmunization with an optimized IL15 plasmid adjuvant enhances humoral immunity via stimulating B cells induced by genetically engineered DNA vaccines expressing consensus JEV and WNV E DIII

The Japanese encephalitis virus (JEV) and West Nile virus (WNV) are responsible for a large proportion of viral encephalitis in humans. Currently, there is no FDA approved specific treatment for either, though there are attempts to develop vaccines against both viruses. In this study, we proposed novel genetically engineered DNA vaccines against these two neurotrophic flaviviruses. The structural domain III (DIII) of E protein from these viruses is reported to carry dominant epitopes that induce neutralizing antibodies. Therefore we created consensus sequence of DIII domain across numerous strains of JEV and WNV. Based on the consensus amino acid sequence, synthetic codon and RNA optimized DIII-expressing DNA vaccine constructs with an efficient leader sequence were synthesized for immunization studies. In addition, we also constructed a genetically engineered IL15 DNA vaccine molecular adjuvant for co-stimulating the immune response against DIII clones. Vaccine constructs were delivered into BALB/C mice intramuscularly followed by electroporation using the CELLECTRA^®in vivo electroporator. We have observed that the combined delivery of both WNV DIII and IL15-ECRO DNA vaccine constructs resulted in not only the highest level of antibody against DIII, but also enhanced cross reactivity with two other antigens tested. Also, coimmunization with IL15 plasmid further increased the immune response by four- to five-fold. Importantly, we have shown that IL15 coimmunization adjuvanted humoral responses against DIII antigens by elevating the level of antibody secreting B cells. Such a DNA vaccine approach may better help to control potential travel related infectious agents such as JEV.     

Antipoliomyelitis immunity status among a population that was regularly vaccinated 11–12 years before

A study of poliomyelitis neutralizing antibodies was carried out on 165 samples of blood serum drawn from subjects aged 14–15 years who had completed vaccination with OPV 11 or 12 years ago.Two different methods of incubation of the serum-virus mixtures (1 hour at 37°C; 6 hours at 37°C and then 18 hours at 4°C, respectively) and two different cell lines (RC-37 and Hep-2) for the inoculation of these mixtures were employed.The results were also evaluated in relation to different initial dilutions of the sera (from 1:4 to 1:1).With the 1:4 initial serum dilution the highest frequencies of sero-negativity were observed utilizing the short incubation time and inoculation in Hep-2 (42% for polio 1,10% for polio 2, 32% for polio 3). These frequencies diminish significantly utilizing the RC-37 cell line and the long incubation respectively.Under all the experimental conditions the results were better when the 1:2 initial serum dilutions were employed and even better when undiluted sera were used. Neutralizing antibodies against the 3 types of poliovirus were detected in the undiluted sera of all the subjects utilizing the long incubation and inoculation in either the RC-37 or the Hep-2 cell lines.In three subjects lacking detectable antibodies at the 1:4 dilution of the sera, the administration of a dose of IPV produced after 5–7 days a high response which remained almost unchanged 30 days later.Corresponding author.     

人巨细胞病毒感染中的细胞免疫机制

人巨细胞病毒(HCMV)在人群中普遍易感,免疫力正常者多为隐性感染,可终身携带病毒.感染后,病毒激活机体免疫系统,产生病毒清除作用.在机体清除HCMV的免疫应答中,与机体其他免疫相比,固有免疫中的免疫细胞和获得性免疫中的细胞免疫起着更为重要的作用,同时巨细胞病毒也通过一系列的逃逸反应来对抗上述免疫的清除作用.     

Immunoglobulin GM and KM genes and measles vaccine-induced humoral immunity

Identifying genetic polymorphisms that explain variations in humoral immunity to live measles virus vaccine is of great interest. Immunoglobulin GM (heavy chain) and KM (light chain) allotypes are genetic markers known to be associated with susceptibility to several infectious diseases. We assessed associations between GM and KM genotypes and measles vaccine humoral immunity (neutralizing antibody titers) in a combined cohort (n = 1796) of racially diverse healthy individuals (age 18–41 years). We did not discover any significant associations between GM and/or KM genotypes and measles vaccine-induced neutralizing antibody titers. African-American subjects had higher neutralizing antibody titers than Caucasians (1260 mIU/mL vs. 740 mIU/mL, p = 7.10 × 10⁻¹³), and those titers remained statistically significant (p = 1.68 × 10⁻⁰⁹) after adjusting for age at enrollment and time since last vaccination. There were no statistically significant sex-specific differences in measles-induced neutralizing antibody titers in our study (p = 0.375). Our data indicate a surprising lack of evidence for an association between GM and KM genotypes and measles-specific neutralizing antibody titers, despite the importance of these immune response genes.