Fourth Booster Dose Research Articles

Knowledge of the Serological Response to the Third BNT162b2 Vaccination May Influence Compliance of Healthcare Workers to Booster Dose.

Previous studies showed that the fourth SARS-CoV-2 vaccine dose has a protective effect against infection, as well as against severe disease and death. This study aimed to examine whether knowledge of a high-level antibody after the third dose may reduce compliance to the fourth booster dose among healthcare workers (HCWs). We conducted a prospective cohort study among HCWs vaccinated with the first three doses at Rambam Healthcare Campus, a tertiary hospital in northern Israel. Participants underwent a serological test before the fourth booster vaccine was offered to all of them, with results provided to participants. The population was divided into two groups, namely those with antibodies below 955 AU/mL and those with 955 AU/mL and higher, a cutoff found protective in a previous study. Multiple logistic regression was carried out to compare the compliance to the fourth booster between the two groups, adjusted for demographic and clinical variables. After adjusting for the confounding variables, the compliance was higher in those with antibody levels below 955 AU/mL (OR = 1.41, p = 0.05, 95% CI 1.10-1.96). In addition, male sex and age of 60 years and above were also associated with higher vaccination rates (OR = 2.28, p < 0.001, 95% CI 1.64-3.17), (OR = 1.14, p = 0.043, 95% CI 1.06-1.75), respectively. Knowledge of the antibody status may affect compliance with the booster dose. Considering waning immunity over time, reduced compliance may affect the protection of HCWs who declined the fourth dose.

Safety and immunogenicity of COReNAPCIN, a SARS-CoV-2 mRNA vaccine, as a fourth heterologous booster in healthy Iranian adults: A double-blind, randomized, placebo-controlled, phase 1 clinical trial with a six-month follow-up

The recurrent COVID-19 infection, despite global vaccination, highlights the need for booster doses. A heterologous booster has been suggested to enhance immunity and protection against emerging variants of concern of the SARS-CoV-2 virus. In this report, we aimed to assess the safety, and immunogenicity of COReNAPCIN, as a fourth booster dose after three doses of inactivated vaccines. MethodsThe study was conducted as a double-blind, randomized, placebo-controlled phase 1 clinical trial of the mRNA-based vaccine candidate, COReNAPCIN. The vaccine was injected as a heterologous booster in healthy Iranian adults aged 18–50 who had previously received three doses of inactivated SARS-CoV-2 vaccines. In the study, 30 participants were randomly assigned to receive either COReNAPCIN in two different doses (25 µg and 50 µg) or placebo. The vaccine candidate contained mRNA encoding the complete sequence of the pre-fusion stabilized Spike protein of SARS-CoV-2, formulated within lipid nanoparticles. The primary endpoint was safety and the secondary objective was humoral immunogenicity until 6 months post-vaccination. The cellular immunogenicity was pursued as an exploratory outcome. ResultsCOReNAPCIN was well tolerated in vaccinated individuals in both doses with no life-threatening or other serious adverse events. The most noticeable solicited adverse events were pain at the site of injection, fatigue and myalgia. Regarding the immunogenicity, despite the seroprevalence of SARS-CoV-2 antibodies due to the vaccination history for all and previous SARS-CoV-2 infection for some participants, the recipients of 25 and 50 µg COReNAPCIN, two weeks post-vaccination, showed 6·6 and 8·1 fold increase in the level of anti-RBD, and 11·5 and 21·7 fold increase in the level of anti-spike antibody, respectively. The geometric mean virus neutralizing titers reached 10.2 fold in the 25 µg group and 8.4 fold in 50 µg group of pre-boost levels. After 6 months, the measured anti-spike antibody concentration still maintains a geometric mean fold rise of 2.8 and 6.3, comparing the baseline levels in 25 and 50 µg groups, respectively. Additionally, the significant increase in the spike-specific IFN-ϒ T-cell response upon vaccination underscores the activation of cellular immunity. ConclusionCOReNAPCIN booster showed favorable safety, tolerability, and immunogenicity profile, supporting its further clinical development (Trial registration: IRCT20230131057293N1).

Immunogenicity of Intradermal Versus Intramuscular BNT162b2 COVID-19 Booster Vaccine in Patients with Immune-Mediated Dermatologic Diseases: A Non-Inferiority Randomized Controlled Trial.

The intradermal route has emerged as a dose-sparing alternative during the coronavirus disease 2019 (COVID-19) pandemic. Despite its efficacy in healthy populations, its immunogenicity has not been tested in immune-mediated dermatologic disease (IMDD) patients. This assessor-blinded, randomized-controlled, non-inferiority trial recruited patients with two representative IMDDs (i.e., psoriasis and autoimmune bullous diseases) to vaccinate with fractionated-dose intradermal (fID) or standard intramuscular (sIM) BNT162b2 vaccines as a fourth booster dose under block randomization stratified by age, sex, and their skin diseases. Post-vaccination SARS-CoV-2-specific IgG and interferon-γ responses measured 4 and 12 weeks post-intervention were serological surrogates used for demonstrating treatment effects. Mean differences in log-normalized outcome estimates were calculated with multivariable linear regression adjusting for their baseline values, systemic immunosuppressants used, and prior COVID-19 vaccination history. The non-inferiority margin was set for fID to retain >80% immunogenicity of sIM. With 109 participants included, 53 received fID (all entered an intention-to-treat analysis). The fID demonstrated non-inferiority to sIM in humoral (mean outcome estimates of sIM: 3.3, ΔfID-sIM [mean, 95%CI]: -0.1, -0.3 to 0.0) and cellular (mean outcome estimates of sIM: 3.2, ΔfID-sIM [mean, 95%CI]: 0.1, -0.2 to 0.3) immunogenicity outcomes. Two psoriasis patients from the fID arm (3.8%) developed injection-site Koebner's phenomenon. Fewer fID recipients experienced post-vaccination fever (fID vs. sIM: 1.9% vs. 12.5%, p = 0.027). The overall incidence of disease flare-ups was low without a statistically significant difference between groups. The intradermal BNT162b2 vaccine is a viable booster option for IMDD patients troubled by post-vaccination fever; its role in mitigating the risk of flare-ups remains unclear.

Effectiveness of a fourth dose of COVID-19 mRNA vaccine in patients with systemic autoimmune rheumatic diseases using disease-modifying antirheumatic drugs: an emulated target trial

Patients with systemic autoimmune rheumatic diseases using disease-modifying antirheumatic drugs (DMARDs) might have blunted responses to COVID-19 vaccines. The initial mRNA vaccine series is defined as three doses for this population and a fourth booster dose is recommended. The effectiveness of the fourth dose in patients with systemic autoimmune rheumatic diseases using DMARDs is not well established. We aimed to assess the effectiveness of receiving versus not receiving a fourth dose of COVID-19 mRNA vaccine using a target trial framework, in a cohort of patients with systemic autoimmune rheumatic diseases receiving DMARD therapy. We conducted an emulated target trial using observational data from the Mass General Brigham health-care system to compare receiving versus not receiving a fourth mRNA vaccine dose. Analysed patients had systemic autoimmune rheumatic diseases, were prescribed DMARDs, and were eligible for a fourth dose of BNT162b2 or mRNA-1273 vaccines between Jan 16 and June 11, 2022. To account for temporal changes, the study period was divided into 1-week intervals. Fourth-dose-exposed patients were included in a 1-week interval if they received a fourth mRNA dose in that interval; fourth-dose-unexposed patients were eligible for but had not received the fourth dose of the vaccine. The primary outcome was a SARS-CoV-2 infection; the secondary outcome was severe SARS-CoV-2 infection (ie, admission to hospital or death within -3 to +14 days of a positive test). We assessed the effectiveness of the fourth dose using time-stratified, overlap propensity score-weighted Cox regression models. We included 4305 patients, 3126 of whom received a fourth dose of vaccine and 1179 who had not. The median follow-up time was 135 days (IQR 112-154) among patients who had received a fourth dose and 65 days (30-156) among patients who had not received a fourth dose. After overlap weighting in both groups, 1863 (72·7%) of 2563 participants were women, 700 (27·3%) were men, and 2242 (87·5%) were White. Rheumatoid arthritis was present in 1392 (54·3%) of 2563 participants; the most frequent treatments were conventional synthetic DMARDs (1489 [58·1%]) or biological DMARDs (1007 [39·3%]). SARS-CoV-2 infection risk was lower among patients receiving versus not receiving a fourth dose of vaccine (HR 0·59 [95% CI 0·47-0·74]). A fourth dose reduced the risk of admission to hospital or death within -3 to +14 days of SARS-CoV-2 infection (0·35 [0·14-0·85]). In this emulated target trial, a fourth dose of COVID-19 mRNA vaccine reduced the risk of SARS-CoV-2 infection and severe COVID-19 among patients with systemic autoimmune rheumatic diseases using DMARDs during the Omicron era. Patients with systemic autoimmune rheumatic diseases should be encouraged to remain up-to-date with COVID-19 vaccinations. The National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

#3161 CLINICAL EFFICACY AND OPTIMAL REGIMEN OF BNT162B2 VACCINE IN CHRONIC DIALYSIS PATIENTS

Abstract Background and Aims Highly effective vaccines against severe acute respiratory syndrome virus 2 (SARS-CoV-2) have been developed and administered worldwide. Protection from coronavirus disease 2019 (COVID-19), however, is not absolute, and optimal vaccination regimens need to be established. Concerns regarding breakthrough COVID-19 disease in vaccinated patients are increasing, as vaccine efficacy appears to gradually decline in the months following vaccination. The emergence of highly infective variants, escalates these issues. This study assessed the clinical efficacy of the BNT162b2 vaccine and all-cause mortality among dialysis patients receiving varying numbers of vaccine doses. Method This study was conducted using the electronic database of Clalit Health Services in Israel. Patients receiving chronic hemodialysis or peritoneal dialysis during COVID-19 pandemic were included in the analysis. The control group consisted of age-and sex-matched individuals, in a 4:1 ratio to the dialysis group. The study included the pre- and post-vaccination periods. Results A total of 14,230 people were included; 2,846 on chronic dialysis and 11,384 controls. Mean age was 66.2±14.3 years (range 18-97). Before the vaccine was available in Israel, 223 dialysis patients were infected with SARS-CoV2. Their mortality rate was 18.4% compared to 10.8% among uninfected, unvaccinated patients in the same period (p = 0.001). On post-vaccination period, we compared the clinical efficacy of a fourth dose to patients who received only 3 doses of BNT162b2 vaccine. SARS-CoV-2 infection rates, hospitalizations due to severe COVID-19, COVID-19–related mortality and all-cause mortality rates were lower among chronic dialysis patients who received a fourth dose of vaccine as compared to those who received only 3 doses (after adjusting for age, sex and comorbidities). Despite lower mortality rates observed with the Omicron variant, an additional booster dose was associated with reduced COVID-19–related mortality (1.7% vs. 3.8%, p = 0.04, HR 0.44 (95% CI 0.2–0.98) in patients who received 4 doses compared to 3 doses. Conclusion As seen in the general population, and with previous vaccine boosters, the fourth dose of the BNT162b2 vaccine reduced rates of severe COVID-19 hospitalization and mortality among chronic dialysis patients. This study strengthens the recommendation to administer a fourth booster dose of vaccine to dialysis patients. Further studies are needed to establish the exact dose and schedule of the COVID-19 vaccine in the vulnerable population patients on chronic maintenance dialysis.

Levels and durability of neutralizing antibodies against SARS-CoV-2 Omicron and other variants after ChAdOx-1 or BNT162b2 booster in CoronaVac-primed elderly individuals

The outbreak of the SARS-CoV-2 Omicron variant raised the need for vaccine boosting. We evaluated the efficiency of the third booster vaccine, ChAdOx-1 or BNT162b2, in causing a neutralizing antibody (NAb) response and its durability against the Omicron and other variants in elderly individuals previously vaccinated with 2-dose CoronaVac inactivated vaccine. After receiving 2-dose CoronaVac, only 2.2% of subjects had NAbs against the Omicron variant above the cut-off value. Four weeks after boosting, the number of subjects who had NAb levels above the cut-off values in the ChAdOx-1 and BNT162b2 vaccine boosting groups increased to 41.7% and 54.5%, respectively. However, after 12 and 24 weeks of boosting with any vaccines, NAb levels against the Omicron variant dramatically waned. Twenty-four weeks after boosting, only 2% had high levels of NAbs against the Omicron variant. Compared to other variants, the Omicron variant was less responsive to boosting vaccines. The waning rate of NAb levels for the Omicron variant was much faster than that observed in the Alpha, Beta and Delta variants. To combat the Omicron variant, the fourth booster dose is, therefore, recommended for elderly individuals.

The Fourth Dose of mRNA COVID-19 Vaccine Following 12 Different Three-Dose Regimens: Safety and Immunogenicity to Omicron BA.4/BA.5

The aim of this study is to investigate the reactogenicity and immunogenicity of the fourth dose using monovalent mRNA vaccines after different three-dose regimens and to compare the 30 µg BNT162b2 and 50 µg mRNA-1273 vaccines. This prospective cohort study was conducted between June and October 2022. The self-recorded reactogenicity was evaluated on the subsequent 7 days after a fourth dose. The binding and neutralizing activity of antibodies against the Omicron BA.4/5 variants were determined. Overall, 292 healthy adults were enrolled and received BNT162b2 or mRNA-1273. Reactogenicity was mild to moderate and well tolerated after a few days. Sixty-five individuals were excluded. Thus, 227 eligible individuals received a fourth booster dose of BNT162b2 (n = 109) and mRNA-1273 (n = 118). Most participants, regardless of the type of previous three-dose regimens, elicited a significantly high level of binding antibodies and neutralizing activity against Omicron BA.4/5 28 days after a fourth dose. The neutralizing activity against Omicron BA.4/5 between the BNT162b2 (82.8%) and mRNA-1273 (84.2%) groups was comparable with a median ratio of 1.02. This study found that the BNT162b2 and mRNA-1273 vaccines can be used as a fourth booster dose for individuals who were previously immunized with any prior three-dose mix-and-match COVID-19 vaccine regimens.

Antibody Titer Correlates with Omicron Infection in Vaccinated Healthcare Workers.

The advent of vaccines against SARS-CoV-2 has drastically reduced the level of hospitalization with severe COVID-19 disease in infected individuals. However, the diffusion of variants of concern still challenge the protection conferred by vaccines raised against the wild-type form of the virus. Here, we have characterized the antibody response to the BNT162b2 (Comirnaty) mRNA vaccine in patients infected with the Omicron variant. We analyzed a population of 4354 vaccinated healthcare workers (HCW) from 7 different hospitals in Italy and monitored infection with SARS-CoV-2 Omicron. We correlated infection with the antibody response after vaccination. We found that a lower level of IgG, younger age, and the presence of allergies correlate with increased infection during the Omicron wave, and that infections correlate with wild-type spike protein antibody titers below 350 BAU/mL. These results support the necessity of a fourth booster dose, particularly for individuals with lower levels of antibodies.

The Four Ws of the Fourth Dose COVID-19 Vaccines: Why, Who, When and What.

With the emergence of SARS-CoV-2 variants, vaccine breakthrough is a major public health concern. With evidence of reduced neutralizing antibody activity against Omicron variants and fading antibody level after the third-dose booster vaccine, there are suggestions of a fourth-dose booster vaccine. In this review, the benefits of a fourth-dose booster is evaluated from four perspectives, including the effectiveness of the booster dose against virus variants (Why), susceptible groups of individuals who may benefit from additional booster dose (Who), selection of vaccine platforms to better enhance immunity (What) and appropriate intervals between the third and fourth booster dose (When). In summary, a fourth dose can temporarily boost the immune response against SARS-CoV-2 variants and can be considered for specific groups of individuals. A heterologous vaccine strategy using mRNA vaccine in individuals primed with inactivated vaccine may boost immunity against variants. The timing of the fourth dose should be individualized but an interval of 4 months after the third-dose booster is appropriate. A universal fourth booster dose is not necessary.

Fourth dose of the SARS-CoV-2 vaccine in kidney transplant recipients with previously impaired humoral antibody response

Fourth dose of the SARS-CoV-2 vaccine in kidney transplant recipients with previously impaired humoral antibody response

Immunogenicity of the third and fourth BNT162b2 mRNA COVID-19 boosters and factors associated with immune response in patients with SLE and rheumatoid arthritis

ObjectivesTo evaluate the safety and immunogenicity of third and fourth BNT162b2 boosters in patients with SLE and rheumatoid arthritis (RA).MethodsPatients with SLE and RA aged 18–65 years who completed a...

Can Thailand achieve COVID-19 herd immunity?

The COVID‐19 outbreak has had a great impact on the social, economic, and health systems of Thailand. A variety of measures to curb the spread of the disease were implemented since the beginning of the pandemic, including a strict national lockdown protocol. The Thai government aimed to achieve herd immunity through an efficient vaccination programme. Initially, vaccine supply shortage and a lack of vaccine options plagued the health system, but this has since been improved. Continuous monitoring of the situation through research is being carried out to assess the level of immunity among the population whereby the current general recommendation is presently a fourth booster dose for adults. Hurdles towards achieving herd immunity remain. One such issue is the low level of vaccine literacy among those that are unvaccinated or inadequately vaccinated. Another obstacle is the sizeable rate of hesitancy towards getting booster doses. Achieving herd immunity in the Thai population would require multilateral cooperation, improved health promotion to target population groups, such as older adults, and a developed distribution system for those with limited access, such as those in the rural areas.

MO224: Antibody Responses to a 3RD Booster Dose of SARS-COV-2 Vaccines in Patients with Vasculitides and Renal Involvement

BACKGROUND AND AIMSImmunosuppressed patients are in general less likely to achieve a detectable antibody response to SARS-CoV-2 after the primary doses of vaccine administration. However, there are limited data for the effect of a third booster dose in this patient population, especially for those with vasculitides and renal involvement treated with rituximab (RTX).METHODWe retrospectively assessed the antibody responses to SARS-CoV-2 vaccination, after completion of the primary vaccine series (two doses) and after the booster third dose, in patients with vasculitides and renal involvement. IgG antibodies to the spike protein S1 subunit of SARS-CoV-2 were measured using ELISA >1 month after completion of the primary vaccination series (two doses of Pfizer or AstraZeneca vaccines) and 15–30 days after the third booster dose (Pfizer, given 3–6 months after the second dose).RESULTSWe included 20 patients with vasculitis [AAV, n = 16 (80%), IgAV, n = 4 (20%)] and renal involvement. All patients received immunosuppressives, including RTX (80%), MMF/AZA (15%), cyclophosphamide (5%), while half of patients were on glucocorticoids. The seroconversion rate after the primary two doses (Pfizer n = 8/16, Astra-Zeneca n = 1/1) was 53%, which increased to 67% after the third booster dose (Pfizer, n = 12/18). Similarly, the median antibody titers increased from 451 U/mL [interquartile range (IQR) 81–10.845] after the second dose to 1016 U/mL (ΙQR: 64–37.568) after the booster dose. Regarding patients treated with RTX, the respective response rates after the second and third dose were 58% and 62%. Seropositive patients after the third dose tended to have lower previous cumulative exposure to RTX compared with seronegative ones (4.55 versus 5.5 g, P = .62, respectively). No vaccine side effects or disease relapses were noted after the three vaccine doses.CONCLUSIONIn our patient cohort with systemic vasculitis and renal involvement treated mainly with RTX, a third booster vaccine dose increased the seropositivity rate from 53% to 67%. Nevertheless, one-third of patients did not achieve seroconversion. Whether a fourth booster dose could benefit these patients is still unknown.

Humoral immunity of BBIBP-CorV (Sinopharm) in kidney transplant recipients: Is it time to revise vaccination strategies.

The mortality of coronavirus disease 2019 (COVID-19) is high in transplant patients, and effective vaccination is aimed to reduce severe disease and mortality. We conducted a cross-sectional study to evaluate humoral and cellular response to two 4-μg doses of BBIBP-CorV vaccine in 100 kidney transplant recipients, using anti-spike IgG, total anti-receptor-binding domain, neutralizing antibody (Ab) level (enzyme-linked immunoassay), and interferon-gamma release assay (IGRA). Seroconversion was evaluated 85.84 ± 30.72 days after the second dose. Note that, 58% of all and 43.05% of infection-naïve participants have developed at least one of the tested antibodies. IGRA was positive in 30.7% of tested transplant recipients. Sixty percent of the participants had either humoral or cellular responses to COVID-19. Only age was independently linked to seropositivity of any degree after vaccination (p<.05). COVID-naïve patients older than 60 years developed significantly less neutralizing Abs. (p = .011). Six patients developed mild COVID infection more than a month after the second dose of the vaccine (54.5 ± 20.8 days). No vaccine-related adverse effects were reported, except self-limited mild to moderate fever and injection site pain. BBIBP-CorV vaccine can be used safely in kidney transplant recipients, although impaired cellular and humoral immunity necessitate adjustments in vaccination strategies, like higher (8-μg doses), fourth booster dose, or boost with different platform vaccine.

Intra-lymphatic administration of GAD-alum in type 1 diabetes: long-term follow-up and effect of a late booster dose (the DIAGNODE Extension trial)

AimTo evaluate the long-term effect of intra-lymphatic administration of GAD-alum and a booster dose 2.5 years after the first intervention (DIAGNODE Extension study) in patients with recent-onset type 1 diabetes.MethodsDIAGNODE-1: Samples were collected from 12 patients after 30 months who had received 3 injections of 4 μg GAD-alum into a lymph node with one-month interval. DIAGNODE Extension study: First in human, a fourth booster dose of autoantigen (GAD-alum) was given to 3 patients at 31.5 months, who were followed for another 12 months. C-peptide was measured during mixed meal tolerance tests (MMTTs). GADA, IA-2A, GADA subclasses, GAD65-induced cytokines, PBMCs proliferation and T cells markers were analyzed.ResultsAfter 30-month treatment, efficacy was still seen in 8/12 patients (good responders, GR). Partial remission (IDAA1c < 9) had decreased compared to 15 months, but did not differ from baseline, and HbA1c remained stable. GAD65-specific immune responses induced by the treatment started to wane after 30 months, and most changes observed at 15 months were undetectable. GADA subclasses IgG2, IgG3 and IgG4 were predominant in the GR along with IgG1. A fourth intra-lymphatic GAD-alum dose to three patients after 31.5 months gave no adverse events. In all three patients, C-peptide seemed to increase the first 6 months, and thereafter, C-peptide, HbA1c, insulin requirement and IDAA1c remained stable.ConclusionThe effect of intra-lymphatic injections of GAD-alum had decreased after 30 months. Good responders showed a specific immune response. Administration of a fourth booster dose after 31.5 months was safe, and there was no decline in C-peptide observed during the 12-month follow-up.

Immunization Coverage Evaluation for the Period of years 2012-2016 in Korce-Albania

Objective: The objective of this study was to evaluate vaccination coverage retrospectively from birth to 14 year-old children for the period of years 2012-2016, considering also some factors that influence vaccine uptake. Methods: Immunization coverage is the proportion of the number of children vaccinated and those scheduled for vaccination. In this study, this value was calculated referring to the national immunization schedule against diphtheria, tetanus, pertussis, Hepatitis B, mumps, rubella and measles for the district of Korca. Results: Vaccine coverage levels referring to this district for MMR vaccine resulted to be 97.4% and for Hepatitis B vaccine resulted to be always above 98%. As for the third dose of the DTP-HepB-Hib vaccine, the average value was found to be 96%. Conclusion: The 2015-2016 period showed an increase in vaccine coverage values for the DTP vaccine. Also, during this period there was a noticeable drop in the coverage levels for the third booster dose of the penta-valent vaccine (DTP-Hep.B-Hib). Vaccine coverage values analyzed for the year 2016 showed a non-optimal continuity regarding to the fourth booster dose of TT/ Td vaccine.

Pneumococcal Polysaccharide Protein D-Conjugate Vaccine (Synflorix™; PHiD-CV)

The pneumococcal polysaccharide protein D-conjugate vaccine (PHiD-CV; Synflorix) contains ten capsular polysaccharide serotypes from the bacterium Streptococcus pneumoniae, eight of which are conjugated to a nonlipidated cell-surface liporotein (protein D) of non-typeable Haemophilus influenzae (NTHi) and two of which are conjugated to either tetanus or diphtheria toxoid. In a three-dose primary vaccination schedule in infants aged <6 months, PHiD-CV elicited high immune responses against all pneumococcal serotypes contained in the vaccine and was noninferior to an approved 7-valent pneumococcal conjugate vaccine (7vCRM) for eight of the ten serotypes (five of the seven common to both vaccines). Moreover, functional antibodies were elicited against all vaccine serotypes in an opsonophagocytic activity (OPA) assay. A fourth booster dose of PHiD-CV during the second year of life elicited an anamnestic response against all ten pneumococcal serotypes, as determined by both antibody concentrations and OPA titers. There were no clinically relevant changes in the immunogenicity of PHiD-CV when coadministered with meningococcal serogroup C conjugate or pentavalent whole cell pertussis combination vaccines, and polio vaccines using two different primary vaccination schedules. 11Pn-PD, an 11-valent prototype of PHiD-CV, demonstrated protection against episodes of acute otitis media (AOM) caused by S. pneumoniae and NTHi in infants aged <27 months. The first occurrence of an episode of AOM caused by pneumococcal vaccine serotypes was reduced by 52.6% in 11Pn-PD vaccinees compared with recipients of a control vaccine (primary endpoint). The tolerability profile of PHiD-CV was generally similar to that of 7vCRM.

Immunogenicity of the 10-Valent Pneumococcal Non-typeable Haemophilus influenzae Protein D Conjugate Vaccine (PHiD-CV) Compared to the Licensed 7vCRM Vaccine

The immunogenicity of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) was assessed and compared with the 7-valent pneumococcal conjugate vaccine (7vCRM). Healthy subjects (1650) were randomized to be vaccinated with 3 doses of PHiD-CV or 7vCRM (Prevenar/Prevnar) at 2-3-4 months of age and a fourth booster dose at 12-18 months. Serotype-specific pneumococcal responses (GlaxoSmithKline's ELISA with 22F-inhibition) and opsonophagocytic activity (OPA) were measured 1 month after primary and booster vaccinations. The primary objective to demonstrate noninferiority of PHiD-CV versus 7vCRM (in terms of percentage of subjects with antibody concentration >or=0.2 microg/mL) for at least 7 of the 10 vaccine serotypes was reached as noninferiority was demonstrated for 8 serotypes. Although, noninferiority could not be demonstrated for ELISA responses against serotypes 6B and 23F, a post-hoc analysis of the percentage of subjects with OPA titers >or=8 suggested noninferiority for the 7 serotypes common to both vaccines including 6B and 23F.Priming of the immune system against all vaccine serotypes was confirmed by robust increases in ELISA antibody levels ( approximately 6.0-17 fold) and OPA titers ( approximately 8-93 fold) after a fourth consecutive dose of PHiD-CV. PHiD-CV induces ELISA and functional OPA antibodies for all vaccine serotypes after primary vaccination and is noninferior to 7vCRM in terms of ELISA and/or OPA threshold responses. Effective priming is further indicated by robust booster responses.

Immunogenicity and safety of four different doses of Haemophilus influenzae type b-tetanus toxoid conjugated vaccine, combined with diphtheria–tetanus–pertussis vaccine (DTP-Hib), in Indonesian infants

Widespread use of Haemophilus influenzae type b (Hib) conjugated vaccine in industrialized countries has resulted in a dramatic decline in the incidence of invasive Hib diseases, but the vaccine's cost has prevented its inclusion in basic immunization programs in developing countries. To overcome this problem, combination with diphtheria–tetanus–pertussis (DTP) vaccine or reduction in the dose of Hib vaccine has been proposed. To evaluate the immunogenicity and adverse reactions from lower doses of Hib-polyribosylphosphate (PRP) conjugated with tetanus toxoid (PRP-T), a double-blind study was conducted in Jakarta, Indonesia, and its suburbs. A total of 1048 infants 6 weeks to 6 months of age received three doses of DTP vaccine combined with the usual 10 μg dose or with a reduced dose of 5, 2.5 or 1.25 μg of PRP-T at two-monthly intervals. Antibodies were measured prior to the first dose and 4–6 weeks following the third dose. Adverse reactions were similar among all four groups. The only significant difference was a higher rate of irritability ( p < 0.02) and of temperature elevation >38 °C ( p < 0.009) after doses 1 and 2 in the lowest dose group (1.25 μg PRP-T) compared to the other groups. All participants tested had a 4-fold increase in antibodies against all DTP antigens. In addition, after a fourth booster dose of Hib, 99.6% of infants produced ≥0.15 μg/ml of antibody to Hib-PRP, and 96.4% showed levels ≥1.0 μg/ml after primary immunization, level that correlate with short- and long-term immunity, respectively. Antibody titers to the PRP antigen showed no significant differences among dosage groups with the exception of the 5.0 μg group, which had a significantly higher GMC than the 1.25 μg group ( p < 0.012). This study demonstrates that primary vaccination with half, one-fourth, or one-eighth of the usual dose of PRP-T, combined with DTP vaccine, produces protective immune responses, and has side effects that are comparable to DTP vaccination alone. In these lower dosages, PRP-T conjugate vaccine can lower vaccine costs to a level that is affordable for infant immunization programs in developing countries.

Accelerated schedule of hepatitis B vaccination in patients with hemophilia

Early development of immunity after hepatitis B vaccination is particularly important for patients such as hemophiliacs, at high risk for acquiring hepatitis B from potentially infectious plasma-derived concentrates. The purpose of this study was to evaluate whether or not protective antibody titers could be achieved quickly and maintained in hemophiliacs by an accelerated vaccination schedule. A yeast-recombinant hepatitis B vaccine (Engerix B, SKF Ritt) was given subcutaneously in the deltoid region and repeated 2 and 6 weeks later to 85 hemophiliacs negative for hepatitis B virus (HBV) markers. After the first 22 patients had been enrolled, a modification of the schedule involving a fourth booster dose 24 weeks after the first dose of vaccine was applied to the next 63 consecutive vaccines. Fifty-three percent of vaccinees had antibody titers to hepatitis B surface antigen (anti-HBs > or = 10 mlU/ml) by week 6, even though the mean titers of anti-HBs were somewhat lower than those achieved historically in normal individuals. The protection rate had increased to 87% by week 10, one month after the third dose of vaccine, and to 93% by week 24. One year after starting vaccination, the rate for the vaccinees who did not receive the fourth booster dose was 71%, and 96% for those who did receive the fourth dose, with only 2 patients not responding despite the booster dose. It is concluded that even though the accelerated schedule of immunization produced rapidly high rates of protective antibody titers, a booster dose is required to obtain higher titers and provide more persistent immunity.