Immunoglobulin G (IgG) subclass antibody responses to pneumococcal vaccines were determined for human subjects in four age groups. The ratios of IgG1/IgG2 antibody concentrations declined with advancing age for all five of the serotypes tested. Protein-conjugate vaccines elicited enhanced IgG antibody responses over plain polysaccharide vaccines in infants but not in adult groups.

Adults were immunized with either baculovirus-expressed, purified recombinant hemagglutinin (rHA) from influenza A/Beijing/32/92 (H3N2) virus or saline placebo and evaluated for humoral and in vitro cellular immune responses. Compared with responses in placebo recipients, vaccinees had greater postvaccination H3(Beijing/32) HA (H3)-specific lymphoproliferation and interleukin (IL)-2, IL-10, and interferon-gamma (IFN-gamma) production. Mean increases in the production of IL-10 (> or = 20-fold) and IL-2 (10-fold) were relatively greater than that of IFN-gamma (4-fold) or IL-4 (no change). Serum H3 antibodies were induced in 80% of rHA recipients, and the rise in antibody titer was significantly correlated with changes in IL-2, IL-10, and IFN-gamma concentrations. Vaccination with rHA only minimally enhanced anti-influenza virus cytotoxic T lymphocyte activity. These data demonstrate that rHA immunization of adults elicits a significant recall response by memory B and T lymphocytes and suggest that the cytokine response to vaccination has a T helper cell type 0-like profile.

OBJECTIVE: To compare in adults more than 50 years old the tolerability and immunogenicity of vaccination with recombinant hepatitis B surface antigen (HBs) compared with vaccination with recombinant hepatitis B protein PreS2+S, and to investigate the safety and immunogenicity of a fourth vaccine dose in poor and non‐responders.DESIGN: Randomized, double‐blind prospective study.SETTING: General clinical research center for outpatient evaluation and vaccination.SUBJECTS: Adults older than age 50 who were in general good health and with no known risk factors for acquiring or serologic evidence of hepatitis B virus infection.INTERVENTION: Subjects were randomized to receive 10 mcg HBs (Recombivax®, Merck, Sharp and Dohme), 12 mcg PreS2+S, or 24 mcg PreS2+S vaccine at 0, 1, and 6 months. Poor and non‐responders (anti‐Hbs < 10 mIU/mL at month 9 and/or 12) were encouraged to receive a fourth vaccine injection.MEASUREMENTS: Diary records of temperature and local and systemic reactions following each vaccination were maintained by all subjects. Anti‐HBs levels were measured by radioimmunoassay before the first injection, at 1, 2, 3, 6, 7, 9, and 12 months after for all subjects, and 1 month after the fourth injection for the group of poor and non‐responders.MAIN RESULTS: Twenty men and nine women (mean age ± SD, 66 ± 8.0 years) were enrolled. Ten subjects received HBs vaccine, nine received 12 mcg PreS2+S vaccine, and 10 received 24 mcg PreS2 + S vaccine. One subject in the HBs group dropped out, and data were analyzed for the remaining 28 subjects. There were no differences in rates of side effects reported by each of the three groups. Overall, minor local adverse reactions occurred in 12 (40%) after at least one of the first three vaccinations. Systemic side effects occurred in five (17%) after the first vaccination, in one after the second, but in none after the third. The 24‐mcg PreS2+S vaccine was not more immunogenic than the HBs vaccine, and the 12‐mcg PreS2+S vaccine was judged inadequate. Nineteen of 22 (86%) poor and non‐responders received a fourth vaccination. Minor local adverse reactions were reported by six (32%), and none reported a systemic side effect. For the 12 subjects receiving a fourth injection of HBs or 24 mcg PreS2 + S vaccine, the proportion of responders 1 month following the fourth injection was greater than for 1 month following the third injection (11 of 12 [92%] versus 12 of 19 [63%], respectively, P < .05).CONCLUSION: For adults more than 50 years of age who have low anti‐HBs levels after three vaccine injections, a fourth injection is well tolerated and results in improved immunogenic response.

Healthy subjects <45 years old (young adults) or >65 (elderly adults) were randomized in double-blind fashion to receive intramuscularly subvirion trivalent influenza vaccine, placebo, or 15, 45, or 135 microgram of the hemagglutinin (HA) of the influenza A/Beijing/32/92 (H3N2) virus expressed in insect cells by a recombinant baculovirus (rHA0). All vaccines were well tolerated. Both young and elderly adults manifested serum hemagglutination-inhibition, virus neutralizing, and HA-specific IgG ELISA antibody responses to rHA0 vaccine. In young adults given 135 microgram of rHA0, the vaccine was significantly more immunogenic than subvirion influenza vaccine. Elderly adults also had increased antibody responses to 135 microgram of rHA0 compared with subvirion vaccine, but the difference was not statistically significant. These results demonstrate that high-dose rHA0 vaccines are well tolerated and effectively induce both functional and binding serum HA-specific antibody in young and elderly adults.

Healthy adults > or = 50 years old were immunized with either pentavalent Corynebacterium diphtheriae C7 (beta197) cross-reactive material (CRM197) protein-conjugated pneumococcal vaccine (CV) containing 10 microgram each of capsular oligosaccharides from serotypes 6B, 14, 18C, 19F, and 23F or with licensed (23-valent, 25 microgram/serotype) pneumococcal polysaccharide vaccine (PV). Adverse reactions, predominantly local in nature, occurred in 20 of 23 CV recipients versus 13 of 23 PV recipients (P<.05). Compared with mean postvaccination antibody concentrations in PV recipients, those induced by CV were not significantly different for serotypes 6B, 14, 18C, and 23F and were lower for 19F (P<.05). Six months later, reimmunization with PV of subjects who had initially received CV elicited a slight boost in antibody concentrations to levels that were not significantly higher than those achieved after the primary vaccination or than those in persons given a single dose of PV. Pneumococcal vaccines containing protein-conjugated oligosaccharides may offer no advantage over currently licensed preparations containing unconjugated polysaccharides for immunization of healthy older adults.

This randomized double-blind study evaluated cytotoxic T lymphocyte (CTL) responses of elderly volunteers after parenteral immunization with either liposome-adjuvanted (n = 23) or control subvirion (n = 26) vaccine containing detergent-split influenza A/Taiwan/1/86 (H1N1) virus, Peripheral blood mononuclear cells obtained 0, 2, and 12 weeks after vaccination were stimulated in vitro with influenza A (H1N1) virus-infected autologous cells and then assayed for influenza virus-specific cytotoxicity using autologous virus-infected target cells, CTL responses to vaccination exhibited influenza A virus heterosubtypic cross-reactivity and were mediated primarily by CD8(+) effector cells, Anti-influenza virus CTL activity was enhanced to a significantly greater extent by the liposome vaccine than by the control subvirion vaccine, It remains to be established whether the advantage of a liposomal formulation in terms of an improved CTL response is relevant to vaccine protective efficacy,

Journal Article Influenza A Virus Vaccines Containing Purified Recombinant H3 Hemagglutinin Are Well Tolerated and Induce Protective Immune Responses in Healthy Adults Get access Douglas C. Powers, Douglas C. Powers Reprints or correspondence: Dr. Douglas C. Powers, VA Medical Center (IIG-JB). Jefferson Barracks Division, 1 Jefferson Barracks Dr., S1. Louis, MO 63125-4199. Search for other works by this author on: Oxford Academic PubMed Google Scholar Gale E. Smith, Gale E. Smith Search for other works by this author on: Oxford Academic PubMed Google Scholar Edwin L. Anderson, Edwin L. Anderson Search for other works by this author on: Oxford Academic PubMed Google Scholar Donald J. Kennedy, Donald J. Kennedy Search for other works by this author on: Oxford Academic PubMed Google Scholar Craig S. Hackett, Craig S. Hackett Search for other works by this author on: Oxford Academic PubMed Google Scholar Bethanie E. Wilkinson, Bethanie E. Wilkinson Search for other works by this author on: Oxford Academic PubMed Google Scholar Franklin Volvovitz, Franklin Volvovitz Search for other works by this author on: Oxford Academic PubMed Google Scholar Robert B. Belshe, Robert B. Belshe Search for other works by this author on: Oxford Academic PubMed Google Scholar John J. Treanor John J. Treanor Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Infectious Diseases, Volume 171, Issue 6, June 1995, Pages 1595–1599, https://doi.org/10.1093/infdis/171.6.1595 Published: 01 June 1995 Article history Received: 28 October 1994 Revision received: 18 January 1995 Published: 01 June 1995

Prototype influenza A H1N1 viruses representing antigenically distinct Hsw1, H0, and H1 hemagglutinin variants that circulated during the early 19O0s were used to measure cross-reactive serum hemagglutination inhibition antibodies elicited by contemporary inactivated virus vaccines in adults aged < 40 (young), 40-64 (middle-aged), or greater than or equal to 65 (elderly) years. Elevated titers of antibodies to Hsw1 and H0 antigens were present both before and after vaccination in higher proportions of middle-aged and elderly than young adults, whereas antibodies to more recent H1 antigens were prevalent in all age groups. Vaccine responses to heterologous H1N1 viruses were consistently reduced in frequency and magnitude with advancing age. Also, within each age group, antibody responses tended to diminish against progressively older heterologous antigens. These results confirm previous seroepidemiological surveys but suggest that preferential orientation of secondary antibodies toward priming epitopes (''original antigenic sin'') is not responsible for the age-related impairment of antibody responses to influenza vaccine.

OBJECTIVE:To investigate whether influenza A-specific cytotoxic T lymphocyte (CTL) activity is reduced in elderly compared with younger adults. DESIGN:Case series comparing outcomes in young and elderly cohorts. SETTING:Saint Louis University Division of Geriatric Medicine. PARTICIPANTS:Healthy adult outpatients and staff members aged < 50 (young) or > or = 65 (elderly) years. METHODS:Peripheral blood mononuclear cells were assayed for CTL activity by a 51chromium release assay following 1 week of in vitro stimulation with influenza A/PR/8/34 (H1N1) virus. MEASUREMENTS:Percent specific lysis of autologous and allogeneic influenza virus-infected target cells. MAIN RESULTS:Specific lysis of autologous A/PR-infected targets was significantly lower in elderly compared to young subjects (P < 0.01), and exceeded 10% in a significantly lower proportion of elderly compared with younger subjects (P < 0.05), but was not influenced by a history of vaccination within the preceding 12 months. Cytotoxic effectors were class I human leukocyte antigen (HLA)-restricted and displayed heterosubtypic cross-reactivity but were unable to lyse influenza B-infected targets. CONCLUSIONS:These results demonstrate an age-related decline of influenza A virus-specific CTL activity and suggest that CTL responses to inactivated virus vaccine are of short duration.

Healthy seropositive adults aged < 40 (n = 15), 40-64 (n = 15), and > or = 65 (n = 17) years were parenterally immunized with trivalent subvirion influenza virus vaccine, and their cellular and humoral immune responses were compared. Vaccination resulted in a significant enhancement of class I human leukocyte antigen-restricted influenza A cross-reactive cytotoxic T lymphocyte (CTL) memory. Elderly subjects had significantly lower baseline and peak postvaccination mean percentages of specific lysis of influenza A virus-infected autologous targets but nonetheless mounted CTL responses to vaccine that were comparable in magnitude to those of younger adults. Serologic responses and nasal IgG responses to each of 3 vaccine strains were reduced in magnitude and frequency with advancing age. Parenteral immunization was ineffective at inducing nasal wash IgA antibodies. Between 2 and 12 weeks after vaccination, serum and nasal antibody titers decreased modestly, although the rate of decline was comparable between age groups. The ability of elderly adults to mount CTL responses after influenza vaccination suggests that T cell effector mechanisms may be an important determinant of vaccine-induced protection against serious illness in this age group.

Journal of the American Geriatrics SocietyVolume 40, Issue 1 p. 81-94 Geriatric Bioscience Immunological Principles and Emerging Strategies of Vaccination for the Elderly Douglas C. Powers MD, Douglas C. Powers MDSearch for more papers by this author Douglas C. Powers MD, Douglas C. Powers MDSearch for more papers by this author First published: January 1992 https://doi.org/10.1111/j.1532-5415.1992.tb01835.xCitations: 37 From the Geriatric Research Education and Clinical Center, Saint Louis VA Medical Center and the Division of Geriatric Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume40, Issue1January 1992Pages 81-94 RelatedInformation

ObjectiveTo compare young and elderly adults in terms of their immune responses and rates of infection following intranasal vaccination with a live attenuated influenza virus.DesignTime series, comparing outcomes in young and elderly convenience sample.MethodRetrospective laboratory analysis of serum and nasal wash specimens collected during prior studies in which young or elderly volunteers had been inoculated with cold‐adapted influenza A/Kawasaki/86 (H1N1) reassortant virus.SettingJohns Hopkins Center for Immunization Research.ParticipantsHealthy young and elderly adults with prevaccination serum hemagglutination inhibition (HAI) antibody titers ≤1:8.Outcome MeasurementsAntibody responses in serum and nasal washes.Main ResultsThe proportion of vaccinees who developed any serum or local antibody response was higher in young compared with elderly subjects (20/20 vs 5/14, P < 0.0005). Resistance to infection with cold‐adapted virus correlated with pre‐vaccination levels of serum immunoglobulin G (IgG), serum IgA, and nasal wash IgA antibody to whole virus antigen. Age was highly correlated with a lack of response to vaccine by simple regression, but not when data were adjusted for pre‐existing antibody levels.ConclusionsCold‐adapted reassortant influenza A H1N1 viruses achieve lower rates of infection in elderly than young adults, primarily due to age‐related differences in preexisting levels of immunity which may not be reflected by HAI titer.

In a double-blind, randomized trial, 102 healthy elderly subjects were inoculated with one of four preparations: (i) intranasal bivalent live attenuated influenza vaccine containing cold-adapted A/Kawasaki/86 (H1N1) and cold-adapted A/Bethesda/85 (H3N2) viruses; (ii) parenteral trivalent inactivated subvirion vaccine containing A/Taiwan/86 (H1N1), A/Leningrad/86 (H3N2), and B/Ann Arbor/86 antigens; (iii) both vaccines; or (iv) placebo. To determine whether local or systemic immunization augmented mucosal immunologic memory, all volunteers were challenged intranasally 12 weeks later with the inactivated virus vaccine. We used a hemagglutination inhibition assay to measure antibodies in sera and a kinetic enzyme-linked immunosorbent assay to measure immunoglobulin G (IgG) and IgA antibodies in sera and nasal washes, respectively. In comparison with the live virus vaccine, the inactivated virus vaccine elicited higher and more frequent rises of serum antibodies, while nasal wash antibody responses were similar. The vaccine combination induced serum and local antibodies slightly more often than the inactivated vaccine alone did. Coadministration of live influenza A virus vaccine did not alter the serum antibody response to the influenza B virus component of the inactivated vaccine. The anamnestic nasal antibody response elicited by intranasal inactivated virus challenge did not differ in the live, inactivated, or combined vaccine groups from that observed in the placebo group not previously immunized. These results suggest that in elderly persons cold-adapted influenza A virus vaccines offer little advantage over inactivated virus vaccines in terms of inducing serum or secretory antibody or local immunological memory. Studies are needed to determine whether both vaccines in combination are more efficacious than inactivated vaccine alone in people in this age group.

Lymphocytes of aged animals exhibit a marked decrease in proliferative capacity in response to mitogen stimulation when compared to those of younger animals. In humans and mice the decreased proliferation is due at least in part (i) to the inability of lymphocytes to synthesize sufficient interleukin 2 (IL-2) and (ii) to decreased expression of IL-2 receptors (IL-2R) on the surface of aged lymphocytes. We compared proliferative abilities, IL-2 production, and IL-2R expression in splenocyte cultures of 4- to 5- and 22- to 24-month-old Fischer 344 rats stimulated with either concanavalin A (Con A) or A23187 and phorbol myristate acetate (PMA). Proliferation was significantly decreased in aged lymphocytes (30–50%) with both treatment protocols. However, unlike mice and humans we observed no difference in IL-2 activity, IL-2 mRNA levels, or IL-2R cell surface expression of lymphocytes from young and aged rats stimulated with either Con A or A23187 and PMA. These results indicate that factors other than decreased expression of IL-2 and IL-2R are responsible for the diminished proliferative capacity of aged rat lymphocytes following mitogen stimulation.

In this communication the binding characteristics and possible regulatory role of sIL2R were investigated. Soluble IL2R are released or secreted in high concentrations by phytohemagglutinin (PHA) stimulated human lymphoid cells. The addition of sIL2R, purified by gel filtration chromatography, to cultures of PHA stimulated lymphoblasts resulted in a dose-dependent inhibition of [3H]TdR incorporation that could be overcome by the addition of exogenous IL2. Scatchard analysis of IL2 binding demonstrated that the presence of sIL2R did not inhibit ligand interaction with the high affinity IL2R. Immunoprecipitation studies utilizing [125I]IL2 and the non-inhibitory anti-Tac protein antibody 7G7/B6 revealed that most of the 125I-labeled IL2 migrated with a protein of approximately 45-50 kDa on SDS/PAGE. Together, these results provide evidence that the sIL2R limits the availability of free IL2 to proliferating cells and down-regulates their response without directly affecting the number or function of the cell bound high affinity IL2R.

High affinity interleukin 2 receptors (HA-IL-2R) on mitogen- or antigen-stimulated T cells have been shown to efficiently bind interleukin 2 (IL-2) and to transduce the activation signal(s) that facilitate proliferation. This study was initiated to determine whether the impaired proliferative response of T cells from elderly individuals can be attributed to the defective expression of HA-IL-2R. While cells from both young and old individuals had statistically insignificant differences in the number of HA-IL-2R per membrane IL-2R-positive cell and these receptors displayed similar binding affinities with 125I-IL-2, there were consistently fewer cells and fewer cells expressing HA-IL-2R in the cell cultures from elderly individuals. The magnitude of the age-associated impairment in cell proliferation was decreased, but remained present, when Percoll fractionated lymphoblasts, as compared to peripheral blood lymphocytes (PBL), were cultured in the presence of exogenous interleukin 2 (IL-2). The results demonstrate that a significantly larger percentage of lymphocytes from elderly individuals do not respond to mitogenic stimulation and, probably due to stimulus stress, die in culture. As a consequence there are fewer functionally competent cells expressing the HA-IL-2R in cultures from elderly individuals, which in turn contributes to the age-related defect in the lymphocyte proliferative response.

Intranasal live attenuated cold-adapted (ca) influenza A/Kawasaki/9/86 (H1N1) reassortant virus and parenteral inactivated influenza A/Taiwan/1/86 (H1N1) virus were given alone or in combination to 80 ambulatory elderly subjects. An enzyme-linked immunosorbent assay was used to measure hemagglutinin-specific (HA) antibodies in serum and nasal wash specimens collected before vaccination and 1 and 3 months later. Serum immunoglobulin G (IgG) and nasal wash IgA HA responses were elicited in 56 and 20%, respectively, of 25 inactivated-virus vaccinees and in 67 and 48%, respectively, of 27 recipients of both vaccines but in only 36 and 25%, respectively, of 28 vaccinees given live virus alone. Inactivated virus, administered alone or with live virus vaccine, induced higher titers of serum antibody than did the live virus alone. In contrast, nasal IgA HA antibody was elicited more often and in greater quantity by the vaccine combination than by either vaccine alone. Despite these differences, the peak titers of local antibody mounted by each group of vaccinees were similar. By 3 months postvaccination, serum IgG and nasal IgA HA antibody titers remained elevated above prevaccination levels in 50 and 17%, respectively, of the inactivated-virus vaccinees and in 46 and 23%, respectively, of recipients of both vaccines but in only 19 and 7%, respectively, of the live-virus and systemic antibodies, if vaccinees. The finding that live ca influenza A virus induced short-lived local and systemic antibodies, if confirmed, suggests that live virus vaccination may not be a suitable alternative or adjunct to inactivated virus vaccination for the elderly.

The levels of interleukin 2 (IL-2), interleukin 2 receptor (IL-2R), and interferon-γ (IFN-γ) specific mRNA and their gene products were examined in phorbol myristate acetate (PMA) and calcium ionophore A23187-costimulated purified T cells from young and elderly humans. In addition, the number of high-affinity IL-2R per activated cell, the high-affinity IL-2R density, and the proliferative response of the cells were measured. Among PMAA23187-stimulated T cells, there was no statistically significant age-related difference in IL-2 or IL-2R specific mRNA accumulation or in the amount of IL-2 or IL-2R synthesized. IFN-γ specific mRNA was increased significantly in T cells from elderly individuals and the amount of IFN-γ synthesized by PMAA23187-activated T cells was nearly double that produced by cells from young individuals. Quantification of the number of high-affinity IL-2R by [125I]IL-2 binding demonstrated there was no decrease in either the mean number or the dissociation constant of the high-affinity IL-2R on activated T cells of the elderly. Despite producing large amounts of IL-2 and having comparable numbers of both low- and high-affinity IL-2R, PMAA23187-stimulated T cells from elderly subjects still proliferated less vigorously than did T cells from young persons. The addition of exogenous IL-2 to the cultured cells did not fully correct this age difference. Our findings that the expression of the IL-2, IL-2R, and IFN-γ genes are not constitutionally defective in the elderly support the hypothesis that the age-related decline in proliferation observed in mitogen-stimulated T cells of the elderly is most likely attributable to alterations in the transmission of signals from the cell membrane to the nucleus.

Normal aging is accompanied by diverse changes in the immune system. Altered function of both T- and B-cells can be shown by losses in proliferative ability and interleukin-2 and interferon synthesis. Granulocyte function is decreased. Although there can be elevations in immunoprotein levels, antibody formation is decreased in most elderly individuals. Response to immunization varies greatly in the aged. This paper discusses the changes in immune function in the elderly, and the clinical implications of these changes.