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L R Haaheim

Publications and source records attributed to L R Haaheim.

At least 19 recordsLinked to original sources
PubMed2007

A comparison of the humoral and cellular immune responses at different immunological sites after split influenza virus vaccination of mice.

The spleen, bone marrow and lymph nodes are all known to be important organs for the initiation and maintenance of an immune response after vaccination. To investigate the differences and similarities in the humoral and cellular immune responses between these tissues, we vaccinated mice once or twice with the conventional human dose (15 microg HA) of influenza A (H3N2) split virus vaccine and analysed the sera and lymphocytes collected from the different sites. We found that the response of antibody secreting cells (ASC) in the lymph nodes appeared to be more transient than in the spleen, possibly because the influenza-specific IgM ASC in particular might have migrated from the lymph nodes immediately after activation. The serum antibody response was found to initially correspond with the ASC response elicited in the spleen and the lymph nodes, whereas the later serum IgG reflected the ASC response in the bone marrow. Proliferation of influenza-specific CD4(+) and CD8(+) cells was predominantly observed in the spleen and was associated with higher concentrations of cytokines than in the lymph nodes. The finding of influenza-specific CD8(+) cell proliferation in the spleen indicates that a split influenza virus vaccine may stimulate a cytotoxic T-cell response. Our results also showed that the primary response elicited a mixed Th1/Th2 profile, whereas the secondary response was skewed towards a Th2 type. Each of the three tissues had a different immunological pattern, suggesting that in preclinical vaccine studies, there is a case for investigating a range of immunological sites.

Animals↗
PubMed2006

Identification of genetic diversity by cultivating influenza A(H3N2) virus in vitro in the presence of post-infection sera from small children.

Antigenic variants probably arise in the field by escaping herd immunity. We have earlier found that sera from small children are more strain-specific than sera from adults and could therefore, provide favourable conditions for selecting antigenic escape mutants. We had access to small volumes of anonymous sera collected in Norway after the epidemic season 1999/00, which was dominated by the A/Panama/2007/99 (H3N2) variant. The HA gene of the representative strain of that season was genetically identical to A/South Australia/147/99 (H3N2) and was selected for this study. Two sera from children aged 4 and 3 years, respectively, and one adult (64 years old) were used to attempt selecting antigenic escape mutants. Virus was grown in MDCK cells in the presence of human serum and escaped variants were tested by haemagglutination-inhibition tests. Although variant strains were occasionally identified, their HA1 genetic sequence did not identify obvious changes at known antigenic sites. However, by cloning and subsequent sequencing, the genetic diversity of the parent virus was found to be significantly reduced when grown in the presence of human sera. Data also showed that the two children's sera selected additional mutants from those already present in the parent pool and that the two sera selected different mutants. On a community level, it is possible that antigenic changes could be accumulated in a step-wise manner when epidemic virus is transmitted from one small child to the next, each with a restricted and possibly variant antibody repertoire.

Animals↗
PubMed2006

Impact of influenza vaccine formulation with a detailed analysis of the cytokine response.

Vaccination provides the most effective method of limiting the impact of influenza. Inactivated influenza vaccines are available in three formulations and more information needs to be generated on how antigen presented in different vaccine formulations influences the subsequent immune response. In the present study, we have investigated the effect of two different influenza vaccine formulations on the resulting antibody and cytokine responses and compared these responses with influenza infection. Mice were vaccinated intramuscularly with one or two doses of whole or split virus vaccine or alternatively intranasally infected with influenza virus. Lymphocytes were isolated from spleen cells and stimulated in vitro for 24 or 72 h for analysis of cytokine profile at the gene expression and at the protein level. Additionally, whole blood was collected and the serum antibody response investigated by haemagglutination inhibition (HI) and enzyme-linked immunosorbent assay (ELISA). We found that one dose of whole virus vaccine induced higher antibody and cytokine responses and thus was more immunogenic in unprimed mice than split virus vaccine. Whole virus vaccine induced a strong IFN-gamma (type 1) immune response after one dose of vaccine and a more mixed cytokine response after the second dose. Split virus vaccine induced a type 2 response, particularly after two vaccine doses. Our results show that two doses of vaccine (both vaccine formulation) were more effective in induction of Th2 type of cytokines and thus indicate that both the formulation and also the number of vaccine doses substantially influences the magnitude and quality of the immune response.

Animals↗
PubMed2005

Whole influenza virus vaccine is more immunogenic than split influenza virus vaccine and induces primarily an IgG2a response in BALB/c mice.

The aim of this study was to compare the kinetics and the magnitude of the humoral immune response to two different influenza vaccine formulations, whole and split virus vaccines. BALB/c mice were immunized intramuscularly with one or two doses (3 weeks apart) of 7.5, 15 or 30 microg of haemagglutinin of monovalent A/Panama/2007/99 (H3N2) split or whole virus vaccine. The two vaccine formulations induced similar kinetics of the antibody-secreting cells response; however, differences in the magnitude were observed in the spleen and bone marrow. Vaccination with whole virus vaccine generally elicited a quicker and higher neutralizing antibody response, particularly after the first dose of vaccine. The two vaccine formulations gave different immunoglobulin G (IgG) subclass profiles. Split virus vaccine stimulated both IgG1 and IgG2a antibodies suggestive of mixed T-helper 1 (Th1) and Th2 response, whereas whole virus vaccine induced mainly an IgG2a antibody response, which is indicative of a dominant Th1 response. The increased immunogenicity of whole virus vaccine in a naïve population could reduce the vaccine concentration needed to provide protective immunity.

Animals↗
PubMed2005

Two doses of parenterally administered split influenza virus vaccine elicited high serum IgG concentrations which effectively limited viral shedding upon challenge in mice.

We have previously found that whole influenza virus vaccine induced a more rapid and stronger humoral response, particularly after the first dose of vaccine, than split virus vaccine in mice. In this study, we have evaluated the protective efficacy of whole and split influenza virus vaccines in mice using a nonlethal upper respiratory tract challenge model. We have also investigated the immunological correlates associated with no or very little viral shedding after viral challenge. Vaccination resulted in reduced viral shedding and shortened the duration of infection by at least 2 days. After one dose of vaccine, whole virus vaccine generally resulted in less viral shedding than split virus vaccine. In contrast, two doses of split virus vaccine, particularly the highest vaccine strengths of 15 and 30 microg HA, most effectively limited viral replication and these mice had high concentrations of prechallenge influenza-specific serum IgG. The vaccine formulation influenced the IgG2a/IgG1 ratio, and this IgG subclass profile was maintained upon challenge to some extent, although it did not influence the level of viral shedding. The concentration of postvaccination serum IgG showed an inverse relationship with the level of viral shedding after viral challenge. Therefore, serum IgG is an important factor in limiting viral replication in the upper respiratory tract upon challenge of an antigenically similar virus.

Animals↗
PubMed2003

Original antigenic sin. A confounding issue?

The 'Doctrine of Original Antigenic Sin', first phrased by Francis, Davenport & Hennessy in 1953, and followed up by occasional papers in the 1960s and 1970s, has lived a life in obscurity and negligence ever since it was postulated. From time to time, and with long intervals, papers on the subject appear. And almost invariably, they are quickly forgotten. Although many will erroneously use the phrase 'Antigenic Sin' to describe classical cross-reactions, the term should be reserved to describe the strain-specific serological response to earlier influenza strains after infection or vaccination with later variants, irrespective of whether one or more antigenic shifts had occurred during the observation period of the study. It is unlikely that antibodies generated under the mechanism of Antigenic Sin will have any major epidemiological relevance.

Antigens, Viral↗
PubMed2002

Non-lethal viral challenge of influenza haemagglutinin and nucleoprotein DNA vaccinated mice results in reduced viral replication.

Influenza DNA vaccines have been widely studied in experimental animal models and protection documented after lethal viral challenge. In this study, we have investigated the humoral response after a non-lethal viral challenge of mice vaccinated with plasmids encoding the influenza haemagglutinin (HA) or nucleoprotein (NP) genes. BALB/c mice were immunized intramuscularly with three doses (100 microg) of HA, NP or backbone plasmid at 3-week intervals, or alternatively infected intranasally, before being challenged with homologous virus 13 weeks later. Mice were then sacrificed at weekly intervals and the antibody-secreting cell response was examined systemically (spleen and bone marrow) and in the respiratory tract (nasal associated lymphoid tissue (NALT) and lungs). Sera were collected after each dose of vaccine and at sacrifice and analyzed by ELISA, haemagglutination inhibition and virus neutralization assays. We found that previous viral infection apparently elicits sterilizing immunity. Vaccination with HA or NP DNA significantly reduced viral replication in the nasal cavity after viral challenge, however, increases in serum antibody titres were observed after challenge. Prior to challenge, specific antibody-secreting cells were observed in the systemic compartment after HA or NP DNA vaccination but were also found in the NALT after viral challenge. In conclusion, intramuscular DNA vaccination resulted in immunological memory in the systemic compartment, which was rapidly reactivated upon viral challenge.

Animals↗
PubMed2001

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.

Administration, Inhalation↗
PubMed1999

The effect of age and natural priming on the IgG and IgA subclass responses after parenteral influenza vaccination.

This study investigated the effect of natural priming and age on serum IgG and IgA subclass responses after parenteral trivalent influenza vaccination. Sera from 18 young children and 8 adults were collected at various times after vaccination. An ELISA was performed to quantify the concentrations of antibody subclasses. The children were divided into primed and unprimed groups based on the presence of prevaccination serum antibodies. In both children and adults, IgG1 and IgA1 were the predominant IgG and IgA subclasses detected after vaccination. No IgG2 responses were detected in sera of unprimed children, and the proportion of the IgG2 response was lower in primed children than in adults. This suggests that the IgG2 immune response in young children is dependent on previous priming and may mature later than the other IgG subclasses after parenteral influenza vaccination.

Adult↗
PubMed1998

Systemic and mucosal immune responses in young children and adults after parenteral influenza vaccination.

The effect of natural mucosal priming on systemic and mucosal immune responses was investigated in young children after parenteral influenza vaccination. Eighteen young children and 8 adults were vaccinated with trivalent influenza vaccine at various time intervals before tonsillectomy. The influenza-specific IgG, IgA, and IgM immune responses were examined in tonsillar lymphocytes and frequent samples of peripheral blood and oral fluid. Young children were divided into primed and unprimed groups on the basis of presence of prevaccination serum antibodies. In peripheral blood, adults and primed children had significantly higher IgG and IgA antibody responses than did unprimed children. Irrespective of priming, children elicited weaker IgA responses than adults in both tonsils and oral fluid. While natural priming was essential to elicit strong systemic response in young children after parenteral influenza vaccination, it did not influence the local responses, which were significantly lower in both primed and unprimed children than in adults.

Adult↗
PubMed1998

Towards a nasal vaccine against meningococcal disease, and prospects for its use as a mucosal adjuvant.

A Norwegian outer membrane vesicle (OMV) vaccine against group B meningococcal disease proved to be strongly immunogenic when administered intranasally in mice. The OMV preparation, made from Neisseria meningitidis and intended for parenteral use, was therefore given without adjuvant to human volunteers (n = 12) in the form of nose drops or nasal spray. Such immunizations, which were carried out at weekly intervals during a three-week period, were able to induce systemic antibodies with bactericidal activity in more than half of the individuals. In addition, all vaccinees developed marked increases in OMV-specific IgA antibodies in nasal secretions. The potential of the OMV particles as carriers for other less immunogenic antigens were elucidated in mice with use of whole inactivated influenza virus. Even though influenza virus alone did induce some systemic and salivary antibody responses after being administered intranasally, these responses were greatly augmented when the virus was presented together with OMVs. Thus, it is possible that a nasal OMV vaccine may induce protection against invasive meningococcal disease, and also that it might be used as a vehicle for nasal vaccines against other diseases.

Adjuvants, Immunologic↗
PubMed1996

[Use of influenza vaccine in Norway].

Following the 1993/94 influenza season a questionnaire study was carried out to evaluate the use of influenza vaccine among at-risk groups. 275,000 doses of influenza vaccine were provided free of charge by the National Institute of Public Health to about 500 municipal health care units. 104 of 150 randomly selected units responded to our questionnaire. A majority correctly estimated the vaccine efficacy to be 70-80%, and 90% of the persons who were vaccinated belonged to the defined target groups. Two of three respondents were in favour of the government's support. Influenza among the target groups was mainly regarded as an individual problem, but considered to be a community issue for the general public. The strain on public health budgets for treatment of the old and infirm during influenza epidemics is obviously not fully appreciated.

Humans↗
PubMed1996

Dynamics of HIV-1 replication following influenza vaccination of HIV+ individuals.

Levels of HIV-1 have been reported to increase in peripheral blood after influenza vaccination of HIV+ individuals. In this study we have evaluated the dynamics of these changes. Ten HIV-1+ individuals classified in revised CDC clinical categories B and C as well as five seronegative healthy controls were vaccinated with the recommended influenza strains. HIV viral RNA and proviral DNA were sequentially quantified in serum and blood lymphocytes, respectively. Nine of the 10 HIV+ individuals had an increase in the frequency of infected CD4 cells 2 weeks after influenza vaccination. Individuals with low viral load had a rapid increase in viraemia and a small increase in frequency of infected cells in peripheral blood. In contrast, individuals with high viral load had a small drop in viraemia followed by a significant rise in the rate of infected cells. The observed change may resemble those taking place during intercurrent infections in HIV+ individuals. The effects of the relative increases in infectious virus after the transient viraemic phase should be further investigated to evaluate potential risks of vaccination.

CD4-Positive T-Lymphocytes↗
PubMed1996

Serum antibodies from patients with primary Sjögren's syndrome and systemic lupus erythematosus recognize multiple epitopes on the La(SS-B) autoantigen resembling viral protein sequences.

The aim of this study was to investigate the epitope recognition pattern of La(SS-B) autoantibodies in sera from patients with Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE) using overlapping synthetic decapeptides on solid phase. Eighty different decapeptides with five amino acids overlap from the human La(SS-B) autoantigen were synthesized on cellulose paper using F-moc chemistry. Tests were performed with 14 SS and six SLE sera. The results showed that the immune response to the La(SS-B) oligopeptides was restricted and unique for each individual with no particular pattern typical for each of the two diseases, apart from the fact that SLE sera gave positive reaction with fewer peptides. Regions within the N- and C-termini harboured most of the positive sequences. The authors specifically addressed the possibility of a viral aetiology for disease development or autoantibody generation. In this context the most frequently recognized linear epitopes on the La(SS-B) autoantigen showed sequence similarities with proteins from a range of ubiquitous human viruses, in particular from the herpes virus group. The La(SS-B) autoantibodies may thus be generated through molecular mimicry.

Adult↗
PubMed1995

Cross-reaction but no avidity change of the serum antibody response after influenza vaccination.

Pre- and post-vaccination sera from 19 volunteers were analysed by the haemagglutination inhibition (HI) test, virus neutralization (VN) assay and avidity enzyme-linked immunosorbent assay (ELISA). The sera were tested against the three strains in a commercial inactivated influenza vaccine; A/Beijing/353/89(H3N2); A/Taiwan/1/86 (H1N1) and B/Yamagata/16/88. Additionally, a range of earlier strains and one newer isolate were assayed for HI- and VN-antibodies. Large variations in the pre-vaccination HI titres were observed for the viruses tested. However, 8-9 days after vaccination HI titres increased to above the assumed protective level (HI > or = 40) in most subjects. Although a limited number of patients were analysed at each sampling point, the time-profile we observed in this study is consistent with data we have obtained in earlier trials (Cox, R.J. et al., Vaccine 1994, 12,993-999). The VN titres, on the other hand, were low against all influenza strains before and up to 6 days, but increased rapidly 8-9 days after vaccination. A recent H3N2 isolate, A/Beijing/32/92 (H3N2), which had drifted further away from the vaccine strain, reacted to low titres or were negative in both the HI and VN assays. No change in the serum avidity to the influenza surface antigens was detected after vaccination, whereas sera from subjects naturally infected with influenza showed an increase in avidity to the infecting virus strain. The increase in serum avidity observed in the infected subjects is probably due to the increased and prolonged antigenic stimulus provided by the replicating virus.

Adolescent↗
PubMed1995

Parenteral influenza vaccination induces a rapid systemic and local immune response.

The kinetics of the local immune response in the upper respiratory tract to parenterally administered inactivated split trivalent influenza vaccine were examined in 19 healthy subjects. Influenza virus-specific antibody-secreting cells (ASC) could be detected as early as 2 days after vaccination in peripheral blood and tonsils, with a peak at approximately 1 week after vaccination and a decline to insignificant levels after 6 weeks. Circulating ASC produced IgG, IgA, and IgM, whereas ASC in tonsils produced mainly IgA and IgM. Influenza virus-specific antibodies were predominantly IgG and IgM in serum and IgA in oral fluid; they rose after 1 week and were elevated at 6 weeks. This may indicate a secretory involvement of the anti-influenza virus response in the upper respiratory tract. Parenteral influenza vaccination induced an immediate and significant immune response in both the upper respiratory tract and peripheral blood.

Adolescent↗
PubMed1994

Norway: problems which a small and sparsely populated European country without a national vaccine production would face during a pandemic.

Since Norway at present has no national influenza vaccine production, there is some concern that during a pandemic influenza situation it would be difficult to secure even a limited quantity of appropriate influenza vaccine. It is conceivable that national emergency directives declared in the manufacturing countries would ban or severely hinder export of a life-saving commodity such as influenza vaccine. Most probably, this would be the situation for all European countries without a national influenza vaccine production. To ensure vaccine availability for the purchasing country even under a national influenza emergency situation declared in the manufacturing country such agreements must be safe against unilateral cancellation.

Aged↗