Immunogenicity of the 13-Valent Pneumococcal Conjugated Vaccine Followed by the 23-Valent Polysaccharide Vaccine in Chronic Lymphocytic Leukemia.

Patients with Chronic Lymphocytic Leukemia (CLL) have a 29- to 36-fold increased risk of invasive pneumococcal disease (IPD) compared to healthy adults. Therefore, most guidelines recommend vaccination with the 13-valent pneumococcal conjugated vaccine (PCV13) followed 2 months later by the 23-valent polysaccharide vaccine (PPSV23). Because both CLL as well as immunosuppressive treatment have been identified as major determinants of immunogenicity, we aimed to assess the vaccination schedule in untreated and treated CLL patients. We quantified pneumococcal IgG concentrations against five serotypes shared across both vaccines, and against four serotypes unique to PPSV23, before and eight weeks after vaccination. In this retrospective cohort study, we included 143 CLL patients, either treated (n = 38) or naive to treatment (n = 105). While antibody concentrations increased significantly after vaccination, the overall serologic response was low (10.5%), defined as a ≥4-fold antibody increase against ≥70% of the measured serotypes, and significantly influenced by treatment status and prior lymphocyte number. The serologic protection rate, defined as an antibody concentration of ≥1.3 µg/mL for ≥70% of serotypes, was 13% in untreated and 3% in treated CLL patients. Future research should focus on vaccine regimens with a higher immunogenic potential, such as multi-dose schedules with higher-valent T cell dependent conjugated vaccines.

Immunogenicity and 1-year boostability of a three-dose intramuscular rabies pre-exposure prophylaxis schedule in adults receiving immunosuppressive monotherapy: a prospective single-centre clinical trial.

BACKGROUND: For immunocompromised patients (ICPs), administration of rabies immunoglobulins (RIG) after exposure is still recommended regardless of prior vaccination, due to a lack of data. We aimed to assess the 1-year boostability of a three-dose rabies pre-exposure prophylaxis (PrEP) schedule in individuals using immunosuppressive monotherapy. METHODS: In this prospective study, individuals on immunosuppressive monotherapy with a conventional immunomodulator (cIM) or a TNF-alpha inhibitor (TNFi) for a chronic inflammatory disease received a three-dose intramuscular PrEP schedule (days 0,7,21-28) with 1 mL Rabipur®, followed by a two-dose simulated post-exposure prophylaxis (PEP) schedule (days 0,3) after 12 months. Rabies neutralizing antibodies were assessed at baseline, on day 21-28 (before the third PrEP dose), day 60, month 12 and month 12 + 7 days. The primary outcome was 1-year boostability, defined as the proportion of patients with a neutralizing antibody titre of ≥ 0.5 IU/mL at month 12 + 7 days. Secondary outcomes were geometric mean titres (GMTs) and factors associated with the primary endpoint. RESULTS: We included 56 individuals, of whom 52 completed the study. The 1-year boostability was 90% (47/52) with a GMT of 6.16 (95% CI 3.83-9.91). All participants seroconverted at some point in the study. Early response to PrEP (at day 21-28) was significantly associated with 100% boostability (Odds Ratio 51; 95% confidence interval [5.0-6956], P < 0.01). The vaccination schedule was safe and well tolerated. No vaccine-related serious adverse events occurred. CONCLUSION: In patients using immunosuppressive monotherapy, a three-dose rabies PrEP schedule followed by a two-dose PEP schedule is immunogenic, with all patients seroconverting at some point in the study. Although boostability 7 days after PEP was not 100%, nobody would wrongly be denied RIG when only administered to those who responded early to PrEP while reducing the administration of RIG by 73%.

Immunogenicity of the 13-valent pneumococcal conjugate vaccine followed by the 23-valent pneumococcal polysaccharide vaccine in people living with HIV on combination antiretroviral therapy.

People living with HIV (PLWH) are at increased risk of pneumococcal infections compared with the general population. The objective of this study was to investigate the immunogenicity of the combined pneumococcal vaccination schedule in PLWH. In this prospective cohort study, adult PLWH on antiretroviral therapy and HIV-negative controls received the 13-valent pneumococcal conjugate vaccine (PCV13) at baseline followed by the 23-valent pneumococcal polysaccharide vaccine (PPSV23) at Month 2. Serotype-specific IgG levels of 24 vaccine serotypes were measured at Months 0, 2, 4, 6 and 12. The primary outcome was seroprotection at Month 4, defined as the proportion of patients with a post-immunisation IgG concentration of ≥1.3 µg/mL for ≥70% (17/24) of vaccine serotypes. Samples of 120 patients were analysed. Seroprotection at Month 4 was 49% (39/80) for PLWH and 82% (28/34) in controls. At Month 12, seroprotection had decreased to 23% (18/79) and 63% (22/35), respectively. Nadir CD4 count ≥200 cells/mm3, preserved kidney function and co-administration of the diphtheria-tetanus-polio (DTP) vaccine were associated with better seroprotection among PLWH. IgG levels both of PLWH and controls (all 24 vaccine serotypes) were significantly higher compared with baseline at all timepoints. Although IgG levels of all 24 vaccine serotypes increased significantly both in PLWH and controls, only a minority of PLWH achieved seroprotection after PCV13 followed by PPSV23. In addition, protective immunity waned rapidly. Further research into alternative vaccinations strategies for PLWH is needed, such as vaccination schedules with higher-valent pneumococcal vaccines. The DTP vaccine may augment pneumococcal vaccination responses.

Immunogenicity of the 13-Valent Pneumococcal Conjugate Vaccine (PCV13) Followed by the 23-Valent Pneumococcal Polysaccharide Vaccine (PPSV23) in Adults with and without Immunosuppressive Therapy.

Immunosuppressive therapy increases the risk of pneumococcal disease. This risk can be mitigated by pneumococcal vaccination. The objective of this study was to investigate the immunogenicity of the 13-valent pneumococcal conjugate vaccine (PCV13), followed by the 23-valent pneumococcal polysaccharide vaccine (PPSV23), in adults with and without immunosuppressive therapy. We performed a prospective cohort study among adults using conventional immunomodulators (cIM), biological immunomodulators (bIM), combination therapy, and controls during 12 months. The primary outcome was seroprotection, defined as the proportion of patients with a postimmunization IgG concentration of ≥1.3 µg/mL for at least 70% (17/24) of the serotypes of PCV13 + PPSV23. We included 214 participants. For all 24 vaccine serotypes, IgG levels increased significantly in both treatment subgroups and controls, with peak seroprotection rates of 44% (combination therapy), 58% (cIM), 57% (bIM), and 82% (controls). By month 12, seroprotection had decreased to 24%, 48%, 39%, and 63%, respectively. Although pneumococcal vaccination with PCV13 + PPSV23 was immunogenic in all treatment groups, impaired vaccination responses were observed in patients using immunosuppressive medication. Apart from the obvious recommendation to administer vaccines before such medication is started, alternative vaccination strategies, such as additional PCV13 doses or higher-valent pneumococcal vaccines, should be investigated.

Immunogenicity of a 5-dose pneumococcal vaccination schedule following allogeneic hematopoietic stem cell transplantation.

The optimal schedule of pneumococcal vaccination after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains controversial. The objective of this study was to investigate the immunogenicity of a 5-dose pneumococcal vaccination schedule in adult allo-HSCT recipients with and without immunosuppressive therapy. In this prospective cohort study, allo-HSCT recipients received four doses of the 13-valent pneumococcal conjugate vaccine (PCV13) and one dose of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) starting 4-6 months after allo-HSCT. PCV13 was administered at T0, T1, T2, and T8 (T = months from enrollment) and PPSV23 at T10. Serum was collected at T0, T4, T8, T10, and T12, and IgG levels were measured for all 24 vaccine serotypes by immunoassay. The primary outcome was overall seroprotection at T12 defined as an IgG concentration ≥1.3 µg/ml for 17/24 vaccine serotypes in allo-HCST recipients with and without immunosuppressive therapy at baseline. Secondary outcomes were serotype-specific seroprotection and dynamics of IgG levels. We included 89 allo-HSCT recipients in the final analysis. Overall seroprotection was 47% (15/32) for patients without immunosuppressive therapy at baseline versus 24% (11/46) for patients with immunosuppressive therapy (p = .03). Seroprotection was higher for PCV13 serotypes (78% and 54% respectively; p = .03) and lower for PPSV23-unique serotypes (28% and 13% respectively; p = .1). IgG concentrations increased significantly over time for all 24 serotypes. Concluding, although immunogenicity of PCV13 serotypes was reasonable, the poor response to PPSV23 serotypes resulted in an insufficient overall response to pneumococcal vaccination for allo-HSCT recipients. Research into vaccination strategies with higher-valent T-cell-dependent pneumococcal vaccines is needed.

Incidence and Predictors of Community-Acquired Pneumonia in Patients With Hematological Cancers Between 2016 and 2019.

BACKGROUND: Patients with hematological cancers (HC) are at high risk of infections, in particular community-acquired pneumonia (CAP). Recent data on incidence and predictors of CAP among patients with HC are scarce. METHODS: We performed a cohort study (2016-2019) in 2 hospitals in the Netherlands among adults with HC to calculate incidence rates (IRs) of CAP. In addition, we performed a nested case-control study to identify predictors of CAP. RESULTS: We identified 275 CAP cases during 6264 patient-years of follow-up. The IR of CAP was 4390/100 000 patient-years of follow-up. Compared with the general population, IR ratios ranged from 5.4 to 55.3 for the different HCs. The case fatality and intensive care unit (ICU) admission rates were 5.5% and 9.8%, respectively. Predictors for CAP in patients with HC were male sex, anemia, lymphocytopenia, chronic kidney disease, cardiovascular disease, autologous and allogeneic stem cell transplantation, treatment with immunosuppressive medication for graft-vs-host disease, treatment with rituximab in the past year, and treatment with immunomodulators (lenalidomide, thalidomide, pomalidomide and/or methotrexate) in the past month. Independent predictors of a severe disease course (death or ICU admission) included neutropenia (odds ratio, 4.14 [95% confidence interval, 1.63-10.2]), pneumococcal pneumonia (10.24 [3.48-30.1]), chronic obstructive pulmonary disease (6.90 [2.07-23.0]), and the use of antibacterial prophylaxis (2.53 [1.05-6.08]). CONCLUSIONS: The burden of CAP in patients with HC is high, with significant morbidity and mortality rates. Therefore, vaccination against respiratory pathogens early in the disease course is recommended, in particular before starting certain immunosuppressive therapies.

Immunogenicity and Reactogenicity of Vaccine Boosters after Ad26.COV2.S Priming.

BACKGROUND: The Ad26.COV2.S vaccine, which was approved as a single-shot immunization regimen, has been shown to be effective against severe coronavirus disease 2019. However, this vaccine induces lower severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (S)-specific antibody levels than those induced by messenger RNA (mRNA)-based vaccines. The immunogenicity and reactogenicity of a homologous or heterologous booster in persons who have received an Ad26.COV2.S priming dose are unclear. METHODS: In this single-blind, multicenter, randomized, controlled trial involving health care workers who had received a priming dose of Ad26.COV2.S vaccine, we assessed immunogenicity and reactogenicity 28 days after a homologous or heterologous booster vaccination. The participants were assigned to receive no booster, an Ad26.COV2.S booster, an mRNA-1273 booster, or a BNT162b2 booster. The primary end point was the level of S-specific binding antibodies, and the secondary end points were the levels of neutralizing antibodies, S-specific T-cell responses, and reactogenicity. A post hoc analysis was performed to compare mRNA-1273 boosting with BNT162b2 boosting. RESULTS: Homologous or heterologous booster vaccination resulted in higher levels of S-specific binding antibodies, neutralizing antibodies, and T-cell responses than a single Ad26.COV2.S vaccination. The increase in binding antibodies was significantly larger with heterologous regimens that included mRNA-based vaccines than with the homologous booster. The mRNA-1273 booster was most immunogenic and was associated with higher reactogenicity than the BNT162b2 and Ad26.COV2.S boosters. Local and systemic reactions were generally mild to moderate in the first 2 days after booster administration. CONCLUSIONS: The Ad26.COV2.S and mRNA boosters had an acceptable safety profile and were immunogenic in health care workers who had received a priming dose of Ad26.COV2.S vaccine. The strongest responses occurred after boosting with mRNA-based vaccines. Boosting with any available vaccine was better than not boosting. (Funded by the Netherlands Organization for Health Research and Development ZonMw; SWITCH ClinicalTrials.gov number, NCT04927936.).

Invasive pneumococcal disease among adults with hematological and solid organ malignancies: A population-based cohort study.

OBJECTIVES: To determine the risk of invasive pneumococcal disease (IPD) in adult cancer patients stratified by type of underlying malignancy, age, and capsular serotype and to assess herd effects of childhood pneumococcal vaccination. METHODS: All adult IPD cases reported to the Dutch pneumococcal surveillance system between 2004 and 2016 were included in this study. IPD incidence rates (IR) stratified by subtype of malignancy were calculated per 100 000 patient-years of follow-up. Incidence rate ratios (IRR) were calculated to compare IRs between groups. RESULTS: A total of 7167 IPD cases were included, of which 1453 were in patients with malignancies. For patients with hematological malignancies (HM) and solid organ malignancies (SOM), IRs were 482/100 000 and 79/100 000, respectively, compared with 15/100 000 in controls. The highest incidence was observed among patients with multiple myeloma, non-Hodgkin lymphoma, chronic lymphocytic leukemia, pancreatic cancer, and lung cancer (3299/100 000, 2717/100 000, 538/100 000, 559/100 000, and 393/100 000, respectively), and in patients ≥50 years old. Among HM patients, the incidence of IPD declined significantly after the implementation of infant pneumococcal vaccination (IRR 0.65, 95% confidence interval 0.51-0.84); among SOM patients, the decline was not statistically significant (IRR 0.88, 95% confidence interval 0.72-1.07). CONCLUSIONS: The IPD disease burden in cancer patients remains high. Large differences in IPD incidence between the different types of cancer demand tailored guidance regarding pneumococcal vaccination.

Comparison of equivalent fractional vaccine doses delivered by intradermal and intramuscular or subcutaneous routes: A systematic review.

BACKGROUND: For certain vaccines, dosing can be reduced by intradermal (ID) immunization without loss of immunogenicity, as an alternative to standard routes of administration. However, a certain level of dose-sparing might also be achieved by reducing doses of intramuscular (IM) or subcutaneous (SC) vaccines. METHOD: We conducted a systematic review comparing identical reduced amounts of antigen delivered by either ID, or IM/SC routes (PROSPERO registration no. CRD42020151725). RESULTS: Of 6015 articles identified, we included 26 articles, covering eight different vaccines. Equivalent immune responses were demonstrated in 19/26 studies, and 7/26 studies suggested inferior immune responses after IM/SC immunization. CONCLUSIONS: We conclude that fractional dosed IM/SC vaccination is at best as immunogenic, but potentially inferior to ID vaccination. The safety profiles were at large comparable, although minor local adverse events were more common after ID delivery. Future vaccine trials, depending on the platform used, should add a fractional dose IM/SC arm, besides a fractional dose ID arm.

[Vaccination of immunocompromised patients: when and when not to vaccinate]. / Vaccinatie van immuungecompromitteerde patiënten.

Immunocompromised individuals are at increased risk of infectious diseases and their complications. The main examples of these are pneumococcal disease and influenza, infections that are both vaccine-preventable. However, responses to vaccination are often impaired in immunocompromised patients. In addition, live-attenuated vaccines, including the measles-mumps-rubella and yellow fever vaccine, cannot be administered to these patients for safety reasons. In view of the decreasing herd immunity caused by a drop in global vaccination coverage, immunocompromised individuals are at increased risk of infections such as measles, especially during travel abroad. Despite these developments, the improved quality of life resulting from novel treatment options means that immunocompromised patients are travelling more and further than ever. It is the responsibility of the treating physician of the immunocompromised individual to ensure that all the required vaccines are provided in time. To this end, the physician may also refer the patient to the general practitioner or travel clinic for the actual vaccination.

Fractional dose of intradermal compared to intramuscular and subcutaneous vaccination - A systematic review and meta-analysis.

BACKGROUND: Vaccine supply shortages are of global concern. We hypothesise that intradermal (ID) immunisation as an alternative to standard routes might augment vaccine supply utilisation without loss of vaccine immunogenicity and efficacy. METHODS: We conducted a systematic review and meta-analysis searching Medline, Embase and Web of Science databases. Studies were included if: licensed, currently available vaccines were used; fractional dose of ID was compared to IM or SC immunisation; primary immunisation schedules were evaluated; immunogenicity, safety data and/or cost were reported. We calculated risk differences (RD). Studies were included in meta-analysis if: a pre-defined immune correlate of protection was assessed; WHO-recommend schedules and antigen doses were used in the control group; the same schedule was applied to both ID and control groups (PROSPERO registration no. CRD42020151725). RESULTS: The primary search yielded 5,873 articles, of which 156 articles were included; covering 12 vaccines. Non-inferiority of immunogenicity with 20-60% of antigen used with ID vaccines was demonstrated for influenza (H1N1: RD -0·01; 95% CI -0·02, 0·01; I2 = 55%, H2N3: RD 0·00; 95% CI -0·01, 0·01; I2 = 0%, B: RD -0·00; 95% CI -0·02, 0·01; I2 = 72%), rabies (RD 0·00; 95% CI -0·02, 0·02; I2 = 0%), and hepatitis B vaccines (RD -0·01; 95% CI -0·04, 0·02; I2 = 20%). Clinical trials on the remaining vaccines yielded promising results, but are scarce. CONCLUSIONS: There is potential for inoculum/antigen dose-reduction by using ID immunisation as compared to standard routes of administration for some vaccines (e.g. influenza, rabies). When suitable, vaccine trials should include an ID arm.

Immunogenicity of the Currently Recommended Pneumococcal Vaccination Schedule in Patients With Inflammatory Bowel Disease.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at increased risk of invasive pneumococcal infections. Therefore, vaccination with the 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) 2 months later is recommended. However, the level of immunogenicity induced by this vaccination schedule in IBD patients with and without immunosuppressive medication remains unclear. METHODS: We prospectively assessed the immunogenicity of PCV13 followed by PPSV23 in IBD patients by measuring serotype-specific pneumococcal immunoglobulin G antibody concentrations at baseline and 4-8 weeks postvaccination. Response to vaccination was defined as a postvaccination antibody concentration ≥1.3 µg/mL for 70% of the measured serotypes. We analyzed the immunogenic effect of 4 different medication regimens: (1) conventional immunomodulators (ie, oral prednisolone >10 mg/day, thiopurines, methotrexate); (2) anti-tumor necrosis factor agents; (3) combination therapy; and (4) no treatment with immunosuppressive agents (control group). RESULTS: One hundred forty-one IBD patients were included, of whom 37 were controls. Adequate response to vaccination was 59% (61/104) in patients using immunosuppressive agents (groups 1-3) vs 81% (30/37) in controls (odds ratio, 0.33 [95% confidence interval, .13-.82]). A combination of different immunosuppressive drugs most severely impaired the immune response to pneumococcal vaccination (response, 52% [15/29]). CONCLUSIONS: Although the sequential vaccination schedule of PCV13 followed by PPSV23 is safe, immunogenic, and thus beneficial in the majority of IBD patients, those receiving immunosuppressive agents, and especially those receiving combination therapy, have an impaired immune response compared to controls. Therefore, preferably, vaccinations should be administered before the initiation of immunosuppressive therapy. CLINICAL TRIALS REGISTRATION: Dutch trial register #6315.

Incidence and Risk Factors for Invasive Pneumococcal Disease and Community-acquired Pneumonia in Human Immunodeficiency Virus-Infected Individuals in a High-income Setting.

BACKGROUND: Although people living with human immunodeficiency virus (PLWH) are at increased risk of invasive pneumococcal disease (IPD) and community-acquired pneumonia (CAP), it is unclear whether this remains the case in the setting of early initiation of combination antiretroviral therapy (cART), at high CD4 cell counts. This is important, as pneumococcal vaccination coverage in PLWH is low in Europe and the United States, despite longstanding international recommendations. METHODS: We identified all CAP and IPD cases between 2008 and 2017 in a cohort of PLWH in a Dutch HIV referral center. We calculated incidence rates stratified by CD4 count and cART status and conducted a case-control study to identify risk factors for CAP in PLWH receiving cART. RESULTS: Incidence rates of IPD and CAP in PLWH were 111 and 1529 per 100 000 patient-years of follow-up (PYFU). Although IPD and CAP occurred more frequently in patients with CD4 counts <500 cells/µL (incidence rate ratio [IRR], 6.1 [95% confidence interval, 2.2-17] and IRR, 2.4 [95% confidence interval, 1.9-3.0]), the incidence rate in patients with CD4 counts >500 cells/µL remained higher compared with the general population (946 vs 188 per 100 000 PYFU). All IPD isolates were vaccine serotypes. Risk factors for CAP were older age, CD4 counts <500 cells/µL, smoking, drug use, and chronic obstructive pulmonary disease. CONCLUSIONS: The incidence of IPD and CAP among PLWH remains higher compared with the general population, even in those who are virally suppressed and have high CD4 counts. With all serotyped IPD isolates covered by pneumococcal vaccines, our study provides additional argumentation against the poor current adherence to international recommendations to vaccinate PLWH.

Hepatitis A vaccine immunogenicity in patients using immunosuppressive drugs: A systematic review and meta-analysis.

INTRODUCTION: Inactivated hepatitis A (HepA) vaccines are very immunogenic in healthy individuals; however, it remains unclear how different immunosuppressive regimens affect HepA vaccine immunogenicity. Our objective was to summarise the current evidence on immunogenicity of HepA vaccination in patients using immunosuppressive drugs. METHODS: We systematically searched the literature for studies on immunogenicity of inactivated HepA vaccines in adults using immunosuppressive drugs. Studies reporting seroconversion rates (SCR) 4-8 weeks after 1 and 2 doses of HepA vaccine in organ transplant recipients and patients with chronic inflammatory conditions were included in a meta-analysis. RESULTS: We included 17 studies, comprising 1,332 individuals. In healthy controls (2 studies), SCRs were 90-94% after the first dose and 100% after the second dose. In organ transplant recipients, SCRs ranged from 0 to 67% after the first dose of vaccine and 0-97% after the second dose. In patients with chronic inflammatory conditions, SCRs ranged from 6% to 100% after the first dose and from 48 to 100% after the second dose of vaccine. Patients using a TNF-alpha inhibitor versus conventional immune-modulators (e.g. methotrexate, azathioprine, corticosteroids) were more likely to seroconvert after the first dose of vaccine (OR12.1 [2.14-68.2]) but not after the second dose of vaccine (OR 0.78 [0.21-2.92]) in a meta-analysis. CONCLUSION: Studies evaluating HepA vaccine immunogenicity in immunosuppressive agents are heterogeneous. Overall, there is an impaired immune response following HepA vaccination in patients using immunosuppressive drugs, especially after only one dose of vaccine and in organ transplant recipients. HepA vaccination should therefore be considered before immunosuppressive therapy. Future research should focus on alternative vaccination regimens and long-term immunogenicity. PROSPERO ID: CRD42018102607.

Response to Hepatitis A Vaccination in Immunocompromised Travelers.

BACKGROUND: Hepatitis A vaccines are highly immunogenic in healthy patients, but there is uncertainty about their immunogenicity in immunocompromised patients. METHODS: Our study included immunocompromised patients who received 1 or 2 hepatitis A vaccinations between January 2011 and June 2013. We assessed factors that influenced the serologic response to vaccination. We performed a literature review of previous studies on hepatitis A vaccination in immunocompromised patients. RESULTS: Of 85 immunocompromised patients, 65 used immunosuppressive drugs, 13 had received stem cell transplants, and 7 were infected with human immunodeficiency virus. After vaccination, 65 of 85 (76.5%) developed antibodies. Tumor necrosis factor α blocker use was associated with better serologic responses than other immunosuppressive drugs. Female patients were more compliant than male patients with postvaccination antibody titer measurements. In 11 relevant studies, antibody responses after the first and second vaccination averaged 37% and 82%, respectively. Factors that negatively influenced serologic response rates were high doses of immunosuppressive drugs, fewer hepatitis A vaccinations, and a short interval between vaccination and antibody measurement. CONCLUSIONS: Immunocompromised patients showed moderate to good serologic responses to hepatitis A vaccination, but may need more time to develop immunity. Tumor necrosis factor α blocker use was associated with better antibody responses than other drugs. Specifically, male patients should be motivated to return for antibody titer measurements.