Effect of sublingual administration of interferon-alpha on the immune response to influenza vaccination in institutionalized elderly individuals

A randomized double-blind placebo-controlled study was conducted to determine the effect of sublingual administration of IFNalpha on the immune response to influenza vaccination in elderly institutionalized individuals. Sublingual administration of 10 million IU of IFNalpha immediately prior to vaccination, reduced the geometric mean haemagglutination inhibitory (HAI) and IgG2 circulating antibody titers, and the secretory IgA (sIgA) response in saliva, to the New York strain of influenza A virus, 21 days post-vaccination, without detectable drug-related local or systemic toxicity. IFN treatment did not inhibit the immune response to the other components of the vaccine; the New Caledonia strain of influenza A virus, or the Jiangsu strain of influenza B virus. At the dose tested sublingual administration of IFNalpha reduces the immune response to influenza vaccination in elderly institutionalized individuals.     

Age-related changes in the immune response to influenza vaccination in a racially diverse, healthy elderly population

Proliferation to phytohemagglutinin (PHA) and cell-mediated responses to influenza vaccine (FLU) were assessed in healthy elderly Caucasians, African Americans, Latinos and young Caucasians before and after immunization. Both PHA- and FLU-induced proliferation were reduced in elderly subgroups. FLU-induced proliferation increased post-vaccination in all elderly, except African Americans, but responses were lower than young. IL-2 and IFN-gamma levels did not change after vaccination of elderly, regardless of race. The altered response to FLU in elderly African Americans, compared to elderly Caucasians and Latinos, indicates that racial background is important when drawing conclusions about immune responses to FLU in mixed elderly populations.     

The weight of obesity on the human immune response to vaccination

Despite the high success of protection against several infectious diseases through effective vaccines, some sub-populations have been observed to respond poorly to vaccines, putting them at increased risk for vaccine-preventable diseases. In particular, the limited data concerning the effect of obesity on vaccine immunogenicity and efficacy suggests that obesity is a factor that increases the likelihood of a poor vaccine-induced immune response. Obesity occurs through the deposition of excess lipids into adipose tissue through the production of adipocytes, and is defined as a body-mass index (BMI) ≥ 30 kg/m². The immune system is adversely affected by obesity, and these “immune consequences” raise concern for the lack of vaccine-induced immunity in the obese patient requiring discussion of how this sub-population might be better protected.     

Mucosal vaccination and immune responses in the elderly

To develop a mucosal vaccine strategy for the elderly, we have compared mucosal and systemic immune responses between aged (12-14 months) and young adult (8-12 weeks) mice. Both aged and young mice were immunized weekly with three oral doses of 1 mg of ovalbumin (OVA) and 10 microg of cholera toxin as adjuvant. Although elevated levels of OVA-specific systemic IgG and mucosal IgA Ab responses were seen in young mice, aged mice showed impaired antigen-specific mucosal and systemic immune responses. These results suggest that mucosal immunity is down regulated in aged mice.     

Effect of Vitamin A supplementation on the immune response to measles vaccination

A randomized controlled trial was conducted in 395 infants aged 9-12 months to determine the effect of Vitamin A supplementation on concurrently administered measles vaccine. Antibody response was measured using the plaque reduction neutralization assay. No statistically significant differences were demonstrated between the immune response in Vitamin A supplemented and unsupplemented children. Unlike some recent studies, we were unable to demonstrate an immune enhancing effect of Vitamin A supplementation. On the contrary, among children who were given Vitamin A, a lower, but statistically non-significant, proportion had protective antibody levels 6 months after vaccination.     

New approaches to understanding the immune response to vaccination and infection

The immune system is a network of specialized cell types and tissues that communicates via cytokines and direct contact, to orchestrate specific types of defensive responses. Until recently, we could only study immune responses in a piecemeal, highly focused fashion, on major components like antibodies to the pathogen. But recent advances in technology and in our understanding of the many components of the system, innate and adaptive, have made possible a broader approach, where both the multiple responding cells and cytokines in the blood are measured. This systems immunology approach to a vaccine response or an infection gives us a more holistic picture of the different parts of the immune system that are mobilized and should allow us a much better understanding of the pathways and mechanisms of such responses, as well as to predict vaccine efficacy in different populations well in advance of efficacy studies. Here we summarize the different technologies and methods and discuss how they can inform us about the differences between diseases and vaccines, and how they can greatly accelerate vaccine development.     

Improved immune responses to influenza vaccination in the elderly using an immunostimulant patch

The elderly have greater morbidity and mortality due to influenza, and respond poorly to influenza vaccination compared to younger adults. This study was designed to determine if the adjuvant heat-labile enterotoxin from Escherichia coli (LT), administered as an immunostimulant (IS) patch on the skin with influenza vaccination, improves influenza immune responses in the elderly. Three weeks following vaccination, hemagglutination inhibition (HAI) responses in LT IS patch recipients showed improvement over those of elderly receiving vaccine alone, as demonstrated by significance or trends in fold rise [A/Panama (P = 0.004), A/New Caledonia (P = 0.09)], seroconversion [A/New Caledonia (63% versus 40%, P = 0.01), A/Panama (54% versus 36%, P = 0.08)] and seroprotection [26%, 20% and 16% greater for the patch group for A/New Caledonia, A/Panama and B/Shandong strains, respectively]. The data suggest that an LT IS patch may further enhance influenza vaccine immune responses in the elderly.     

Negative effect on immune response of repeated influenza vaccination and waning effectiveness in interseason for elderly people

BackgroundThrough test negative designs for visiting a doctor because of influenza-like illness, many studies have found decreasing efficacy of repeated vaccination. Furthermore, waning effectiveness during interseason periods has been reported. This study was conducted to confirm negative effects of repeated vaccination in individuals with the same vaccine strain and to measure waning effects.MethodsOur cohort includes 66 participants older than 65 years old recruited from an outpatient department of one hospital. All were vaccinated, with hemagglutination inhibition (HI) antibody titers measured from 2001/02 season through the 2003/04 season. HI antibody titers were measured three times in one season: pre-vaccination, post-vaccination, and post-epidemic. To test negative effects of immune response to the repeated vaccination, differences between protection rates and differences between response rates were analyzed for individuals in the two consecutive seasons. For the test of waning effectiveness, we measured the difference in geometric mean titers of HI antibody between post-epidemic results and pre-vaccination results obtained in the following season.ResultsProtection rates were 40–55% in A/New Caledonia/20/99 and ≥75% in A/Panama/2007/99 by repeated vaccination. In A/New Caledonia/20/99 and A/Panama/2007/99 in the 2003/04 season, significant decreases were found in protection rates from the earlier seasons, although the rate for A/Panama/2007/99 in the 2002/03 season increased significantly from that of the prior season. The respective response rates in the 2003/04 season in A/New Caledonia/20/99, and in the 2002/03 and 2003/04 seasons in A/Panama/2007/99 decreased significantly from those of earlier seasons. Regarding waning effectiveness, antibody titers for A/New Caledonia/20/99 in 2003/04 season, and A/Panama/2007/99 in 2002/03 and 2003/04 seasons decreased significantly to 37.0–66.7%.ConclusionResults show significant negative effects of immune response by repeated vaccination and show significant waning effectiveness during the interseason for individuals with the same strain of influenza type A. The proportion of elderly people with HI antibody titers of ≥1:40 might be maintained by repeated influenza vaccination.     

The effect of zanamivir treatment on the early immune response to influenza vaccination

Zanamivir is licensed for influenza treatment, but may also play a role in prophylaxis either alone or in combination with vaccine in epidemic periods. We conducted a double blind placebo controlled trial to investigate the effect of zanamivir treatment on the humoral immune response to influenza vaccine. Forty young healthy volunteers were vaccinated with licensed trivalent influenza vaccine and received 20 mg zanamivir (24 subjects) or placebo (16 subjects) daily for a period of 14 days. No significant differences were observed in the magnitude or the time course of the antibody response to the influenza H3N2 and B strains between the two groups, in contrast the placebo group responded with higher antibody titres to the H1N1. Our results suggest that during an influenza epidemic, volunteers would only need to continue zanamivir treatment for the initial 12 days after vaccination whilst the vaccine induced protective antibody response developed.     

Immune response to influenza vaccination in community-dwelling Chinese elderly persons

We investigated the immune antibody response to influenza vaccine in community-dwelling Chinese elderly persons in Hong Kong. One hundred and twenty-eight subjects were recruited in a single-blind, randomized, and placebo-controlled trial. There was no significant baseline difference between the vaccine and placebo groups regarding the seroprotection rates (PR) (haemagglutination inhibition [HI] titre>or=1:40) and geometric mean titres (GMT) of the HI antibody titers. The PR, GMTs and serological response rates increased significantly in the vaccinated versus placebo groups in A-H1N1 at both weeks 4 and month 6. The GMTs and serological response rates but not the PR for A-H3N2 and influenza B increased significantly in vaccinated versus placebo group at week 4 and month 6 post-vaccination. Multivariate logistic regression analyses of the seroconversion rate for A-H3N2 within the vaccinated group showed that gender, coronary heart disease and the serum albumin level were significant predictors (p=0.018, 0.009 and 0.025, respectively). Influenza vaccination provoked a protective HI antibody response in community-living Chinese elderly persons. The mean number of unplanned hospital admissions per subject over 6 months was significantly lower in the vaccinated than in the placebo groups. Hospitalized elderly persons had poorer nutrition, 4-week post-immunization HI antibody titres and lower mini-mental state examination (MMSE) score than non-hospitalized elderly persons. Logistic regression analyses showed that chronic obstructive airway disease significantly increased the risk of hospitalization while the serum albumin level and 4-week A-H3N2 PR (HI>or=40) were independent predictors of a decreased risk of hospitalizations.     

The immune response to rabies virus infection and vaccination

Infection with rabies virus causes encephalitis in humans that has a case fatality rate of almost 100%. This inability to resolve infection is surprising since both pre-exposure vaccination and, if given promptly, post-exposure vaccination is highly effective at preventing encephalitic disease. The principal immunological correlate of protection produced by vaccination is neutralizing antibody. T-helper cells contribute to the development of immunity whereas cytotoxic T cells do not appear to play a role in protection and may actually be detrimental to the host. One reason for a failure to protect in humans may be the poor immunological response the virus provokes, despite the period between exposure to virus and the development of disease being measured in months. Few individuals have measurable neutralizing antibody on presentation with disease, although in many cases this develops as symptoms become more severe. Furthermore, when antibody is detected in serum it rarely appears in cerebrospinal fluid suggesting limited penetration into the CNS, the site where it is most needed. The role of the modest mononuclear cell infiltrate into the brain parenchyma is unclear. Some studies suggest the virus can suppress cell-mediated immunity early during the infection although there is little mechanistic evidence to support this beyond suppression of intracellular interferon production by the viral phosphoprotein. In contrast, levels of antibody in the CNS correlate to the peak virus production within the CNS. Here we review the current understanding of immune responses to rabies infection and vaccination against this disease. This article identifies a need to understand how rabies antigens are initially presented and how this can influence the subsequent development of antibody responses. This could help identify ways in which the response to prophylactic vaccination can be enhanced and how the natural immune response to infection can be boosted to combat neuroinvasion.     

Antibody response to influenza vaccination in the elderly: a quantitative review

We performed a quantitative review of 31 vaccine antibody response studies conducted from 1986 to 2002 and compared antibody responses to influenza vaccine in groups of elderly versus younger adults. We did a weighted analysis of the probability of vaccine response (measured as seroconversion and seroprotection) for each vaccine component (H1, H3 and B antigens). Using a multiple regression model, we adjusted for factors that might affect the vaccine response. The adjusted odds-ratio (OR) of responses in elderly versus young adults ranged from 0.24 to 0.59 in terms of seroconversion and seroprotection to all three antigens. The CDC estimates of 70-90% clinical vaccine efficacy in young adults and these estimates suggest a corresponding clinical efficacy in the elderly of 17-53% depending on circulating viruses. We conclude that the antibody response in the elderly is considerably lower than in younger adults. This highlights the need for more immunogenic vaccine formulations for the elderly.     

Immune response to influenza vaccination in a large healthy elderly population

Elderly individuals not only demonstrate a greater risk of morbidity and mortality from influenza than the young, but also have greater difficulty mounting a protective response to influenza vaccine. The mechanism of the decreased efficacy of influenza vaccination in the elderly is not well understood. The present study was designed to assess the interaction between cell-mediated and humoral immune responses to influenza vaccine in a large population (n = 233) of healthy elderly individuals (mean age = 80.7) living in six continuing care retirement communities (CCRCs). While influenza vaccination resulted in significant increases in the mean anti-influenza antibody titres and mean proliferative responses of peripheral blood mononuclear cells to purified subvirion trivalent influenza vaccine one month after vaccination, only 48.9% and 30.0% of subjects had intact humoral and cell-mediated immune responses, respectively. No association was observed between intact cell-mediated and humoral responses: 14.7% of subjects had an intact cell-mediated, but not humoral response, and 32.6% of subjects had an intact humoral, but not cell-mediated response. However, IFNgamma production was significantly correlated with both antibody and cell-mediated responses to influenza vaccination, a finding not previously reported in the elderly. These results indicate that there is considerable heterogeneity among immune responses of the elderly to influenza vaccination. This heterogeneity needs to be a major consideration in evaluation of new vaccine preparations.     

Effects of a nutritional supplement on the immune response and cytokine production in free-living Chilean elderly

BACKGROUND: Immune response is impaired in the elderly. Our aim was to study the effects of a special nutritional formula on the immune response and response to influenza and pneumococcal vaccination in elderly subjects. METHODS: Sixty healthy subjects aged > or = 70 years, with a Mini Mental score > or = 22 were studied. Half of the subjects received a special nutritional formula (in addition to the regular diet) providing, among other nutrients, 480 kcal, 31 g proteins, 120 IU vitamin E, 3.8 microg vitamin B12, 400 microg folic acid, 10(9) cfu Lactobacillus paracasei (NCC 2461), and 6 g of fructo-oligosaccharides. At 4 months of follow-up, subjects were vaccinated against influenza and pneumococcus. Lymphokine production by mononuclear cells (PBMC), lymphocyte subpopulations, and natural killer cell (NK) activity were measured at baseline and 4 months of follow-up (before vaccination). Antibodies against influenza and pneumococcal antigens and flu-stimulated production of interferon gamma and interleukin-2 by PBMC were measured at 4 and 6 months. Skin response to 7 recall antigens and body composition were assessed at baseline and at 4 and 12 months. All infections occurring during the study period were recorded. RESULTS: NK activity increased in supplemented subjects and decreased in nonsupplemented individuals. Interleukin-2 production by PBMC and the proportion of T cells with NK activity decreased in controls and did not change in supplemented subjects. Supplemented subjects reported less infections than nonsupplemented individuals (in 13% and 22% of scheduled visits, respectively; p = .02). CONCLUSIONS: This nutritional supplement increased innate immunity and protection against infections in elderly people.     

Infection and immune response in the elderly.

A number of immunologic functions have been shown to decline in an age-related fashion, particularly cell-mediated immunity and antibody response to an immunogen. Underlying degenerative diseases and medications further contribute to the immunologic abnormalities noted in the elderly. The elderly in hospitals and nursing homes are a particularly vulnerable subset, with a high incidence of institutionally acquired infection. Aspects of disease prevention in the elderly are discussed.     

Polylactide-co-glycolide (PLG) microparticles modify the immune response to DNA vaccination

Priming with the major surface glycoprotein G of respiratory syncytial virus (RSV) expressed by recombinant vaccinia leads to strong Th2 responses and lung eosinophilia during viral challenge. We now show that DNA vaccination in BALB/c mice with plasmids encoding G attenuated RSV replication but also enhanced disease with lung eosinophilia and increased IL-4/5 production. However, formulating the DNA with PLG microparticles reduced the severity of disease during RSV challenge without significantly lessening protection against viral replication. PLG formulation greatly reduced lung eosinophilia and prevented the induction of IL-4 and IL-5 during challenge, accompanied by a less marked CD4+ T cell response and a restoration of the CD8+ T cell recruitment seen during infection of non-vaccinated animals. After RSV challenge, lung eosinophilia was enhanced and prolonged in mice vaccinated with DNA encoding a secreted form of G; this effect was virtually prevented by PLG formulation. Therefore, PLG microparticulate formulation modifies the pattern of immune responses induced by DNA vaccination boosts CD8+ T cell priming and attenuates Th2 responses. We speculate that PLG microparticles affect antigen uptake and processing, thereby influencing the outcome of DNA vaccination.     

Impact of probiotics on the immune response to influenza vaccination is strongly influenced by ageing

Influenza vaccination in the over 65s suffers from low success rates because of the age‐associated decline in immunity. Strategies for improving the response to vaccination are therefore urgently needed. Emerging evidence suggests that alteration of the gut microbiota could potentially influence antiviral defences and modulate the outcome of viral infections. Research conducted as part of a Biotechnology and Biological Sciences Research Council (BBSRC) Diet and Health Research Industry Club (DRINC)‐funded project identified immunoregulatory properties of a novel probiotic (B. longum infantis CCUG 52486) and demonstrated that the immune response to this and other probiotics was highly dependent on the age of the donor. Older subjects had a markedly poorer response to influenza vaccination than young subjects and, although a pre‐ and probiotic combination (synbiotic) did not improve the response, there were trends for differential effects of the probiotic in young and older subjects. However, further interrogation revealed that the older subjects on the synbiotic were already at a significant disadvantage in terms of likely ability to respond to the vaccine compared with those randomised to the placebo because of differences in immunosenescence between the randomised groups at baseline. This may have influenced the outcome of the intervention and the implications of this observation are far reaching as it suggests that failure to fully understand subject phenotype could lead to incorrect interpretation of data. The work therefore provides valuable insight into the influence of baseline subject characteristics – particularly immune phenotype – on the outcome of the intervention and highlights the need for more detailed immunological markers for prospective randomisation of subjects.     

Age related differences in the immune response to vaccination and infection with Mycoplasma gallisepticum

Several studies have suggested that there are age related differences in the responses of chickens to vaccination and infection with Mycoplasma gallisepticum, but there have not been any systematic comparisons of the responses of young birds to vaccination with those of birds the same age to infection. The aim of the studies described here was to examine the immune responses of chickens between 1 and 6 weeks of age to vaccination and to infection with M. gallisepticum. Birds under 4 weeks of age developed significantly more severe clinical signs after infection with virulent M. gallisepticum than birds that were 4 or 6-weeks old at the time of infection, with greater concentrations of M. gallisepticum in the trachea. Chickens younger than 4 weeks old at the age of vaccination were protected from clinical signs of disease after challenge and from development of more severe lesions in the trachea and air sacs, although this protective immunity was significantly less effective in controlling the replication of M. gallisepticum in the trachea. Examination of the subsets of lymphocytes infiltrating the tracheal mucosa did not detect any age related differences. Thus the ts-11 vaccine has been shown to be safe in birds between 1 and 4 weeks of age and to be effective in preventing development of severe disease in them after challenge, even though birds of the same age were more susceptible to development of disease when infected with virulent M. gallisepticum.     

Relation of chronic disease and immune response to influenza vaccine in the elderly

The ability of elderly patients to mount an adequate immune response to influenza vaccine has been debated. We studied the serum haemagglutination inhibition (HI) antibody response in elderly persons to determine whether different degrees of chronic illness were a critical factor in immune response. In autumn 1986, trivalent split virus vaccine was used to immunize 87 healthy ambulatory elderly adults and 53 institutionalized elderly adults. The pre-vaccination health status of the healthy elderly group was significantly better as measured by the incidence of chronic disorders and drug use (p less than 0.02) and by the Chronic Health Evaluation component of the APACHE severity of disease classification (p less than 0.001). No group differences were observed in serum HI antibody after immunization with the trivalent influenza vaccine. However, in 28 patients from each group who received the monovalent A/Taiwan/86(H1N1) vaccine 1 month after the trivalent vaccine, the percentage with a postvaccination HI titre greater than or equal to 40 was 57% (16 of 28) for the healthy elderly vs 7% (2 of 28) for the institutionalized elderly (p = less than 0.001). Geometric mean postvaccination HI titres were 31 and 13, respectively (p = 0.004). We concluded that the institutionalized elderly in our study mounted an inferior immune response against the new heterotypic influenza A/Taiwan strain when compared to healthy elderly adults. The Chronic Health Evaluation score may be an effective predictor of a poor immune response to new influenza vaccine strains in the elderly. Increasing age per se and lack of a history of prior influenza immunization did not adversely affect the development of protective levels of serum antibody.(ABSTRACT TRUNCATED AT 250 WORDS)