Antibody responses after first and second Covid-19 vaccination in patients with chronic lymphocytic leukaemia

B-cell chronic lymphocytic leukaemia (CLL) is associated with immunosuppression and patients are at increased clinical risk following SARS-CoV-2 infection. Covid-19 vaccines offer the potential for protection against severe infection but relatively little is known regarding the profile of the antibody response following first or second vaccination. We studied spike-specific antibody responses following first and/or second Covid-19 vaccination in 299 patients with CLL compared with healthy donors. 286 patients underwent extended interval (10–12 week) vaccination. 154 patients received the BNT162b2 mRNA vaccine and 145 patients received ChAdOx1. Blood samples were taken either by venepuncture or as dried blood spots on filter paper. Spike-specific antibody responses were detectable in 34% of patients with CLL after one vaccine (n = 267) compared to 94% in healthy donors with antibody titres 104-fold lower in the patient group. Antibody responses increased to 75% after second vaccine (n = 55), compared to 100% in healthy donors, although titres remained lower. Multivariate analysis showed that current treatment with BTK inhibitors or IgA deficiency were independently associated with failure to generate an antibody response after the second vaccine. This work supports the need for optimisation of vaccination strategy in patients with CLL including the potential utility of booster vaccines.Subject terms: Translational research, Adaptive immunity, Chronic lymphocytic leukaemia     

Immunogenicity of vaccination against influenza, Streptococcus pneumoniae and Haemophilus influenzae type B in patients with multiple myeloma

Vaccination against influenza and Streptococcus pneumoniae is recommended for elderly and immunocompromised individuals. However, there is little information concerning the efficacy of vaccination in specific groups of patients. In this study, 52 patients underwent vaccination against influenza, S. pneumoniae and Haemophilus influenzae type b (Hib) as they attended hospital outpatient clinics. Serum was analysed prior to vaccination and 4-6 weeks afterwards. Antibody titres against S. pneumoniae and Hib were compared with reference values corresponding to the geometric mean titres of a healthy UK population. For influenza vaccination, haemagglutination inhibition (HI) titres were measured against three inactivated strains; a titre of > or = 1/40 was considered protective. No patient had protective titres to all three antigens prior to vaccination and 41 patients (85%) had titres < 1/40 to all 3 strains. Post vaccination only 9/48 patients (19%) achieved protective antibody titres. Resistance to S. pneumoniae and response to Pneumovax II was also poor: prevaccination, 45 patients (93%) had suboptimal antibody titres and in 26/43 patients (61%) titres remained low post vaccination. Resistance to Hib and response to vaccination was comparable with the healthy adult UK population. These results question the practice of routine influenza and pneumococcal vaccination in myeloma patients.     

Effects of the BTN162b2 mRNA COVID-19 vaccine in humoral and cellular immunity in patients with chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL), the most common leukemia in the western countries, is characterized by immunosuppression due to disease itself and cytotoxic treatments. Since the beginning of COVID-19 pandemic, patients with CLL appear to be a vulnerable population. In addition, phase III mRNA vaccine trials did not provide information about the efficacy in immunocomprised population. In CLL, the antibody-mediated response to SARS-CoV-2 vaccine is impaired. The goal of this study was to evaluate the effects of SARS-CoV-2 vaccination on humoral immune response and on cellular immunity in CLL patients. Humoral immune response to BNT162b2 messenger RNA COVID-19 vaccine was evaluated in 44 CLL patients comprising 20 treatment-naïve, 14 under treatment with ibrutinib and 10 in follow-up after completion of therapy. A positive serological response to SARS-CoV-2 vaccination with IgG titers higher than 13 UA/ml was detected in 54.6% of CLL patients with a higher response in patients who obtained remission after treatment. Reduced antibody response was detected in patients under ibrutinib treatment. T-cell response to overlapping pool of peptides representing the spike region was assessed in paired CLL samples collected before and after 1 month from the second dose of COVID-19 vaccine in treatment-naïve and ibrutinib-treated CLL patients using cytokine secretion assay. Both CD3+ CD4+ and CD3+ CD8+ T cells are able to mount a cellular response to spike peptides with secretion of IFNγ and TNFα before and after vaccination in both treatment naïve and ibrutinib-treated patients and this cellular immune response is independent by COVID-19 vaccination. Collectively, T cell response to spike peptides appeared more blunted in CLL patients under treatment with ibrutinib compared to untreated ones. Our study supports the need for optimization of vaccination strategy to achieve an adequate immune response keeping strict preventive measures by CLL patients against COVID-19.     

Vaccination against infections in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a well-defined mature B-cell neoplasm associated with increased susceptibility to infections. Two major options in prevention of infections in CLL, intravenous gammaglobulin treatment and antimicrobial chemoprophylaxis, have not resulted in satisfactory outcome. A third strategy, antimicrobial vaccination, is the topic of this minireview. We collected articles and their references concerning CLL vaccination from the Medline database starting from 1966 and thirteen relevant studies were found. Plain bacterial polysaccharide vaccines would seem to be ineffective in antibody formation in patients with CLL. However, protein and conjugate vaccines appear to be more immunogenic and their responses may be further enhanced with ranitidine adjuvant treatment. New well-designed investigations are needed to develop appropriate vaccination strategies and evaluate vaccination efficacy in infection morbidity and mortality in CLL.     

Haemophilus influenzae type B vaccination and risk of childhood leukaemia in a vaccine trial in Finland

Incidence of childhood leukaemia was studied among subjects of a trial comparing administration of several doses of a conjugate vaccine against Haemophilus influenzae type b (Hib) starting at an early age (three months) with a single dose given at the age of two years. Among 114 000 subjects, a total of 77 cases of childhood leukaemia were detected. The incidence of childhood leukaemia was lower in the early vaccination arm (relative risk 0.72, 95% confidence interval 0.46-1.13) than late vaccination arm, but the difference did not reach statistical significance. Our results suggest that early immunization against Hib may reduce the incidence of childhood leukaemia, but confirmatory studies are needed.     

Vaccination of high-risk breast cancer patients with mucin-1 (MUC1) keyhole limpet hemocyanin conjugate plus QS-21.

Our objective was to determine whether an immune response can be generated against MUC1 peptide and against tumor cell MUC1 after vaccination with MUC1-keyhole limpet hemocyanin (KLH) conjugate plus QS-21 in breast cancer patients. Nine patients with a history of breast cancer but without evidence of disease were treated with MUC1-KLH conjugate plus QS-21, containing 100 microg of MUC1 and 100 microg of QS-21. s.c. vaccinations were administered at weeks 1, 2, 3, 7, and 19. Peripheral blood was drawn at frequent intervals to assess antibody titers. Skin tests were placed at weeks 1, 3, 9, and 21 to determine delayed type hypersensitivity reactions. Common toxicities included a local skin reaction at the site of the vaccine, usually of 4-5 days' duration, and mild flu-like symptoms usually of 1-2 days' duration. High IgM and IgG antibody titers against synthetic MUC1 were detected. IgG antibody titers remain elevated from a minimum of 106-137 weeks after the first vaccination. Binding of IgM antibody to MCF-7 tumor cells was observed in seven patients, although there was minimal binding of IgG antibody. Two patients developed significant antibody titers post-high-dose chemotherapy and stem cell reinfusion. There was no evidence of T cell activation. This MUC1-KLH conjugate plus QS-21 was immunogenic and well tolerated in breast cancer patients. Additional trials are ongoing to determine the optimal MUC1 peptide for use in larger clinical trials. Further investigation of vaccine therapy in high-risk breast cancer is warranted.     

Multiple-dose granulocyte-macrophage-colony-stimulating factor plus 23-valent polysaccharide pneumococcal vaccine in patients with chronic lymphocytic leukemia: a prospective, randomized trial of safety and immunogenicity

BACKGROUND: For the current study, the authors sought to determine whether administration of multiple-dose granulocyte-macrophage-colony-stimulating factor (GM-CSF) could improve response to standard 23-valent polysaccharide pneumococcal vaccine (PPV) in patients with chronic lymphocytic leukemia (CLL). METHODS: Patients were allocated randomly to receive PPV either alone or with 3 doses of GM-CSF (250 microg) given before or after vaccination. Serum was obtained before, 4 weeks after, and 12 weeks after vaccination for antibody determination. Thirty-two patients with CLL were given PPV. They were randomized to receive 3 doses of GM-CSF either before or after vaccination or to receive no GM-CSF. RESULTS: A 4-fold rise in immunoglobulin G (IgG) to capsular polysaccharides from Streptococcus pneumoniae types 4, 6B, 9V, 14, 19F, and 23F occurred in <10% of patients in each of the 3 groups. There were no differences in geometric mean IgG levels in any of the 3 groups 4 weeks or 12 weeks after vaccination. CONCLUSIONS: In patients with CLL, the response to pure polysaccharide pneumococcal vaccine was low despite immune enhancement with multiple doses of GM-CSF. In all patients, reactogenicity was minor.     

Two booster dose hepatitis B virus vaccination in patients with leukemia

The aim of this study was to interpret the antibody response to hepatitis B (HB) vaccination following a two booster dose schedule in 94 acute lymphoblastic leukemia (ALL) patients. All patients were between 1-16 years of age with negative hepatitis B virus (HBV) serology and normal hepatic function. Fifty patients were vaccinated with Engerix B vaccine, and 44 patients were vaccinated with GenHevac B vaccine, with a schedule of 0, 1, 6 and 0, 1, 2, as well as booster doses, in 12 and 6 months respectively. A second booster was given as a fifth dose to 16 unresponsive patients in each vaccine group, 3 and 6 months after the first booster for Engerix B and GenHevac B vaccines respectively. Dosage was 20 microg HbsAg for all patients. Seroconversion rates with protective level antibody were 35.1% (n=33/94). The figures were 32.1% (n=16/50) and 38.6% (n=17/44) for Engerix B and GenHevac B vaccines, respectively. Seroconversion rate in patients younger than 10 years old was found to be higher (39.11%) than older patients (24%), but this was not statistically significant. This study indicates that one third of the leukemic children undergoing maintenence chemotherapy responded to HB vaccine with protective titers of anti-HBs. We recommend HB vaccination especially in developing countries.     

Response to anti-SARS-CoV-2 mRNA vaccines in multiple myeloma and chronic lymphocytic leukemia patients

Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) patients have increased morbidity and mortality rates of COVID-19 due to immunosuppression associated with the disease and ongoing therapy. The same immune impairment accompanying CLL and MM also affects suboptimal vaccine response. The study assessed the effectiveness of the humoral and T cell-mediated immunity following mRNA COVID-19 vaccination (using either BNT162b2 or mRNA-1273) in short-term (2-5 weeks after second dose) and long-term follow-up (12 weeks after vaccination). Between March and August 2021, blood samples were obtained from 62 CLL and 60 MM patients from eight different hematology departments in Poland. Total anti-RBD antibodies were detected in 37% MM patients before vaccination, increased to 91% and 94% in short- and long-term follow-up, respectively. In CLL, serological responses were detectable in 21% of patients before vaccination and increased to 45% in the short-term and 71% in long-term observation. We detected a tendency to higher frequencies of specific CD8+ T cells against SARS-CoV-2 after vaccination compared to samples before vaccination in MM patients and no changes in frequencies of specific T cells in CLL patients. Our study provides novel insights into mRNA vaccination efficacy in immunocompromised MM and CLL patients, and our findings highlight that specific CD8+ T cells against SARS-CoV-2 might be induced by vaccination but do not correlate positively with serological responses.     

Generation of murine monoclonal antibodies to Haemophilus influenzae type b capsular polysaccharide by in vivo immunization

Haemophilus influenzae type b (Hib) is a pathogenic gram-negative bacterium associated with human disease, especially in young children. Protective immune response to Hib results from antibodies developed against the polyribosylribitol phosphate (PRP) capsular polysaccharide of the bacterium. Several investigators in the study of immune response to Hib have produced human monoclonal antibodies to PRP. Only two previous groups have reported the generation of murine anti-PRP monoclonal antibodies using either immunizing mice with inactivated Hib bacteria or a combination of in vivo and in vitro immunization of mice with PRP conjugate antigen (PRP-D). In this present study, we generated murine anti-PRP monoclonal antibody secreting hybridomas for the first time by simple in vivo immunization with PRP conjugate antigen (PRP-T). The anti-PRP antibodies from one hybridoma clone (B10) are further characterized and potential applications are discussed.     

Immune biomarkers to predict SARS-CoV-2 vaccine effectiveness in patients with hematological malignancies

There is evidence of reduced SARS-CoV-2 vaccine effectiveness in patients with hematological malignancies. We hypothesized that tumor and treatment-related immunosuppression can be depicted in peripheral blood, and that immune profiling prior to vaccination can help predict immunogenicity. We performed a comprehensive immunological characterization of 83 hematological patients before vaccination and measured IgM, IgG, and IgA antibody response to four viral antigens at day +7 after second-dose COVID-19 vaccination using multidimensional and computational flow cytometry. Health care practitioners of similar age were the control group (n = 102). Forty-four out of 59 immune cell types were significantly altered in patients; those with monoclonal gammopathies showed greater immunosuppression than patients with B-cell disorders and Hodgkin lymphoma. Immune dysregulation emerged before treatment, peaked while on-therapy, and did not return to normalcy after stopping treatment. We identified an immunotype that was significantly associated with poor antibody response and uncovered that the frequency of neutrophils, classical monocytes, CD4, and CD8 effector memory CD127low T cells, as well as naive CD21+ and IgM+D+ memory B cells, were independently associated with immunogenicity. Thus, we provide novel immune biomarkers to predict COVID-19 vaccine effectiveness in hematological patients, which are complementary to treatment-related factors and may help tailoring possible vaccine boosters.Subject terms: Haematological cancer, Tumour immunology     

Efficacy of Severe Acute Respiratory Syndrome Coronavirus-2 Vaccine in Patients With Thoracic Cancer: A Prospective Study Supporting a Third Dose in Patients With Minimal Serologic Response After Two Vaccine Doses

IntroductionCoronavirus disease 2019 resulted in a 30% mortality rate in patients with thoracic cancer. Given that patients with cancer were excluded from serum antisevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccine registration trials, it is still unknown whether they would develop a protective antispike antibody response after vaccination. This prospective vaccine monitoring study primarily aimed to assess humoral responses to the SARS-CoV-2 vaccine in patients with thoracic cancer.MethodsSARS-CoV-2–spike antibodies were measured using the Abbot Architect SARS-CoV-2 immunoglobulin G immunoassay before the first injection of BNT162b2 mRNA vaccine, at week 4, and 2 to 16 weeks after the second vaccine dose administration. The factors associated with antibody response were analyzed.ResultsOverall, 306 patients, with a median age of 67.0 years (interquartile range: 58–74), were vaccinated. Of these, 283 patients received two vaccine doses at 28-day intervals. After a 6.7-month median follow-up, eight patients (2.6%) contracted proven symptomatic SARS-CoV-2 infection, with rapid favorable evolution. Of the 269 serologic results available beyond day 14 after the second vaccine dose administration, 17 patients (6.3%) were still negative (<50 arbitrary units/mL, whereas 34 (11%) were less than 300 arbitrary units/mL (12.5th percentile). In multivariate analysis, only age (p < 0.01) and long-term corticosteroid treatment (p = 0.01) were significantly associated with a lack of immunization. A total of 30 patients received a third vaccine dose, with only three patients showing persistently negative serology thereafter, whereas the others exhibited clear seroconversion.ConclusionsSARS-CoV2 vaccines were found to be efficient in patients with thoracic cancer, most of them being immunized after two doses. A third shot given to 1% of patients with persistent low antibody titers resulted in an 88% immunization rate.     

Association of WT1 IgG antibody against WT1 peptide with prolonged survival in glioblastoma multiforme patients vaccinated with WT1 peptide

We previously evaluated Wilms’ tumor gene 1 (WT1) peptide vaccination in a large number of patients with leukemia or solid tumors and have reported that HLA‐A*24:02 restricted, 9‐mer WT1‐235 peptide (CYTWNQMNL) vaccine induces cellular immune responses and elicits WT1‐235‐specific cytotoxic T lymphocytes (CTLs). However, whether this vaccine induces humoral immune responses to produce WT1 antibody remains unknown. Thus, we measured IgG antibody levels against the WT1‐235 peptide (WT1‐235 IgG antibody) in patients with glioblastoma multiforme (GBM) receiving the WT1 peptide vaccine. The WT1‐235 IgG antibody, which was undetectable before vaccination, became detectable in 30 (50.8%) of a total of 59 patients during 3 months of WT1 peptide vaccination. The dominant WT1‐235 IgG antibody subclass was Th1‐type, IgG₁ and IgG₃. WT1‐235 IgG antibody production was significantly and positively correlated with both progression‐free survival (PFS) and overall survival (OS). Importantly, the combination of WT1‐235 IgG antibody production and positive delayed type‐hypersensitivity (DTH) to the WT1‐235 peptide was a better prognostic marker for long‐term OS than either parameter alone. These results suggested that WT1‐235 peptide vaccination induces not only WT1‐235‐specific CTLs as previously described but also WT1‐235‐specific humoral immune responses associated with antitumor cellular immune response. Our results indicate that the WT1 IgG antibody against the WT1 peptide may be a useful predictive marker, with better predictive performance in combination with DTH to WT1 peptide, and provide a new insight into the antitumor immune response induction in WT1 peptide vaccine‐treated patients.     

Assessment of humoral immunity to poliomyelitis, tetanus, hepatitis B, measles, rubella, and mumps in children after chemotherapy

BACKGROUND: To evaluate the effect of chemotherapy on humoral immunity to vaccine-preventable disease, the authors investigated the persistence of protective antibody titers in a group of patients who were alive and well after they were treated for pediatric malignancies. METHODS: Serum antibody levels were evaluated for polio, tetanus, hepatitis B, rubella, mumps, and measles in 192 children. The terms lack of immunity and loss of immunity, respectively, were used to describe the absence of immunity in patients who were tested only after chemotherapy and in patients who were tested both before and after chemotherapy and determined to have immunity before chemotherapy. RESULTS: Overall, the absence of a protective serum antibody titer for hepatitis B, measles, mumps, rubella, tetanus, and polio was detected in 46%, 25%, 26%, 24%, 14%, and 7% of patients, respectively. On univariate analysis, loss of antibodies against rubella, mumps, and tetanus was associated significantly with younger age (P < 0.001, P = 0.02, and P = 0.001, respectively), and loss of antibodies against measles was significantly associated with younger age and female gender (P = 0.0003 and P = 0.008, respectively). The administration of 59 booster vaccinations to 51 patients who had lost > or = 1 protective antibody titer resulted in an overall response rate of 93%. CONCLUSIONS: Chemotherapy induced different rates of loss of protective antibody titers depending on the type of vaccination administered. This finding may be responsible for the failure of vaccination programs for patients who have undergone chemotherapy. The administration of a booster dose after the completion of chemotherapy is a simple and cost-effective way to restore humoral immunity against most vaccine-preventable diseases.     

Induction of high-titer IgG antibodies against multiple leukemia-associated antigens in CML patients with clinical responses to K562/GVAX immunotherapy

The ability to target myeloid leukemia with immunotherapy would represent a significant therapeutic advance. We report here immunological analysis of clinical trials of primary and secondary vaccination with K562/GM-CSF immunotherapy in adult chronic phase chronic myeloid leukemia patients (CML-CP) with suboptimal responses to imatinib mesylate. Using serological analysis of recombinant cDNA expression libraries of K562 with autologous vaccinated patient serum, we have identified 12 novel chronic myeloid leukemia-associated antigens (LAAs). We show that clinical responses following K562/GM-CSF vaccination are associated with induction of high-titer antibody responses to multiple LAAs. We observe markedly discordant patterns of baseline and induced antibody responses in these identically vaccinated patients. No single antigen was recognized in all responses to vaccination. We demonstrate that an additional ‘booster'' vaccination series can be given safely to those with inadequate responses to initial vaccination, and is associated with more frequent induction of IgG responses to antigens overexpressed in K562 vaccine compared with primary CML-CP. Finally, those with induced immune responses to the same LAAs often shared HLA subtypes and patients with clinical responses following vaccination recognized a partially shared but non-identical spectrum of antigens; both findings have potentially significant implications for cancer vaccine immunotherapy.     

Clinical Efficacy of a Vaccine-Immunostimulant Combination in the Prevention of Influenza in Patients with Chronic Obstructive Pulmonary Disease and Chronic Asthma

Abstract

Influenza is a leading cause of morbidity and mortality in patients with chronic respiratory diseases. This study compares two influenza prevention schemes in patients with chronic obstructive pulmonary disease and chronic asthma. We enrolled 66 patients, distributed as follows: Group A: 32 subjects treated with influenza vaccine; Group B: 34 patients treated with influenza vaccine and bacterial immunostimulant. The rate of influenza episodes was recorded. Hemoagglutination inhibiting antibody titers for vaccine strains H1N1, H3N2, and B were determined at time 0 (prior to vaccination), and on days 30 and 90 following vaccination. We observed a lower rate of influenza episodes in Group B patients (8.82%) compared to Group A (31.25%) (p<0.05). At day 90 Group B patients presented higher geometric mean antibody titers for strains H1N1 (p=0.07) and H3N2 (p=0.08). Bacterial immunostimulants appear as possible adjuvants in the prevention of influenza episodes, and may prolong antibody response to influenza vaccine strains.     

COVID-19 Vaccine Responses in Patients With Plasma Cell Dyscrasias After Complete Vaccination

IntroductionDue to functional hypogammaglobulinemia, patients with multiple myeloma are at increased risk for infection and generally have poorer responses to vaccines. In this study, we examined antibody responses after complete COVID-19 vaccination in patients with plasma cell dyscrasias, most of whom were receiving treatment.Patients and MethodsReal world study of consecutive patients with multiple myeloma and other plasma cell dyscrasias (PCD) were evaluated after complete vaccination with either the 2-shot mRNA vaccines from BioNTech and Moderna or the 1-shot adenoviral vector vaccine from Johnson & Johnson (J&J). Patients received vaccines 1-4 months before antibody testing without controlling for the type of vaccine or the timing of drug therapy. Patients with a clinical history or antibody evidence of prior infection were excluded. Antinucleocapsid and quantitative anti-spike antibody levels were measured with the Roche Elecys assay.ResultsNinety-five percent of patients had detectable antibody responses. Multivariate analysis showed that higher age, ongoing anti-CD38 monoclonal antibody therapy and the J&J vaccine negatively affected quantitative response. A small number of ineffectively vaccinated patients receiving IVIG subsequently had detectable nucleocapsid and spike antibodies confirming the presence of the latter in currently administered IVIG.ConclusionsNearly all PCD had detectable anti-spike antibodies after vaccination but age, anti-CD38 monoclonal antibody therapy, and the single-shot J&J vaccine negatively affected responses. In patients who received the J&J vaccine, second doses or heterologous mRNA vaccines should be tested. Quantitative antibody testing might make future management more rational, particularly in patients with poor responses.     

Infant vaccinations and risk of childhood acute lymphoblastic leukaemia in the USA.

Previous studies have suggested that infant vaccinations may reduce the risk of subsequent childhood leukaemia. Vaccination histories were compared in 439 children (ages 0-14) diagnosed with acute lymphoblastic leukaemia (ALL) in nine Midwestern and Mid-Atlantic states (USA) between 1 January 1989 and 30 June 1993 and 439 controls selected by random-digit dialing and individually matched to cases on age, race and telephone exchange. Among matched pairs, similar proportions of cases and controls had received at least one dose of oral poliovirus (98%), diphtheria-tetanus-pertussis (97%), and measles-mumps-rubella (90%) vaccines. Only 47% of cases and 53% of controls had received any Haemophilus influenzae type b (Hib) vaccine (relative risk (RR) = 0.73; 95% confidence interval (CI) 0.50-1.06). Although similar proportions of cases (12%) and controls (11%) received the polysaccharide Hib vaccine (RR = 1.13; 95% CI 0.64-1.98), more controls (41%) than cases (35%) received the conjugate Hib vaccine (RR = 0.57; 95% CI 0.36-0.89). Although we found no relationship between most infant vaccinations and subsequent risk of childhood ALL, our findings suggest that infants receiving the conjugate Hib vaccine may be at reduced risk of subsequent childhood acute lymphoblastic leukemia. Further studies are needed to confirm this association and, if confirmed, to elucidate the underlying mechanism.     

Safety and immunogenicity of a DNA vaccine encoding carcinoembryonic antigen and hepatitis B surface antigen in colorectal carcinoma patients.

Despite an abundance of preclinical data, relatively little is known regarding the efficacy of DNA vaccination in humans. Here, we present results from a dose-escalation clinical trial of a dual expression plasmid encoding carcinoembryonic antigen (CEA) and hepatitis B surface antigen (HBsAg) in 17 patients with metastatic colorectal carcinoma. CEA was selected as a prototypic tumor-associated self-antigen, and the HBsAg cDNA was included as a positive control for immune response to the DNA vaccine without relying upon breaking tolerance to a self-antigen. Groups of 3 patients received escalating single i.m. doses of the DNA vaccine at 0.1, 0.3, and 1.0 mg. Subsequent groups of 3 patients received three repetitive 0.3- or 1.0-mg doses at 3-week intervals. A final group of 2 patients received three repetitive 2.0 mg doses at 3-week intervals. Toxicity was limited to transient grade 1 injection site tenderness, fatigue, and creatine kinase elevations, each affecting a minority of patients in a non-dose-related manner. Repetitive dosing of the DNA vaccine induced HBsAg antibodies in 6 of 8 patients, with protective antibody levels achieved in four of these patients. CEA-specific antibody responses were not observed, but 4 of 17 patients developed lymphoproliferative responses to CEA after vaccination. No objective clinical responses to the DNA vaccine were observed among this population of patients with widely metastatic colorectal carcinoma. Nevertheless, this pilot trial has provided encouraging human immune response data in support of this vaccine technology.     

BTLA expression declines on B cells of the aged and is associated with low responsiveness to the trivalent influenza vaccine

Virus-neutralizing antibody and B cell responses to influenza A viruses were measured in 35 aged and 28 middle-aged individuals following vaccination with the 2012 and 2013 trivalent inactivated influenza vaccines. Antibody responses to the vaccine strains were lower in the aged. An analysis of B cell subsets by flow cytometry with stains for immunoregulators showed that B cells of multiple subsets from the aged as compared to younger human subjects showed differences in the expression of the co-inhibitor B and T lymphocyte attenuator (BTLA). Expression of BTLA inversely correlated with age and appears to be linked to shifting the nature of the response from IgM to IgG. High BTLA expression on mature B cells was linked to higher IgG responses to the H1N1 virus. Finally, high BTLA expression on isotype switched memory B cells was linked to better preservation of virus neutralizing antibody titers and improved recall responses to vaccination given the following year.