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Immunity to Chlamydia pneumoniae induced by vaccination with DNA vectors expressing a cytoplasmic protein (Hsp60) or outer membrane proteins (MOMP and Omp2).

Immune responses induced by intramuscular DNA immunization with Chlamydia pneumoniae genes coding for the major outer membrane protein (MOMP), cysteine-rich outer membrane protein 2 (Omp2) or the heat shock protein 60 (Hsp60) were studied. BALB/c mice were vaccinated intramuscularly three times at 3-week intervals and challenged intranasally 2 weeks after the last injection. Immunization with pmomp or phsp60 showed 1.2-1.5 log reduction in the mean lung bacterial counts after the challenge. Specific antibodies were detected only in sera of the mice immunized with pomp2 and phsp60. Although immunization with pomp2 resulted in a strong serum antibody response against Omp2 protein, it failed to protect the mice. Immunization with any of the three vaccines did not reduce the severity of histologically assessed pneumonia, but resulted in significantly higher lymphoid reaction in the lung indicating immunological memory.

Animals↗

Immunogenicity and reactogenicity of diphtheria, tetanus and pertussis toxoids combined with inactivated polio vaccine, when administered concomitantly with or as a diluent for a Hib conjugate vaccine.

In an open trial, 400 infants were randomized to vaccination with a combined diphtheria-tetanus-pertussis-inactivated polio vaccine (DTaP-IPV) either mixed with a Haemophilus influenzae type b (Hib) tetanus toxoid conjugate immediately before injection (DTaP-IPV/Hib (mix)) or given concurrently with the Hib conjugate at separate injection sites (DTaP-IPV+Hib (sep)). The pertussis component consisted of pertussis toxoid alone. The vaccines were given intramuscularly at 3, 5 and 12 months of age. No vaccine-related serious adverse events occurred. Local reactions were evaluated from diary cards completed by the parents. Infants who received DTaP-IPV/Hib (mix) experienced fewer local reactions. Sera were obtained 28-45 days after the second and third vaccinations. Total Hib capsular antibodies were similar in the two groups after the second injection but lower in the group receiving DTaP-IPV/Hib (mix) than in the group receiving DTaP-IPV+Hib (sep) after the third injection (geometric mean 6.1 vs 10.4 microg/ml). Mixing of the vaccines also led to somewhat lower diphtheria toxin antibodies (5.9 vs. 7.7 IU/ml after the third injection) while tetanus antibodies were higher (3.9 vs. 2.5 IU/ml after the third injection). Antibodies against pertussis toxin and the three polio virus types were similar in the two groups. The moderate impairment of the Hib antibody response caused by mixing of the Hib conjugate with aluminium adsorbed DTaP may be due to physicochemical interference but is probably of little clinical importance because of the ability of the Hib conjugates to induce an immunologic memory.

Antibodies, Bacterial↗

Planning, registration, and implementation of an immunisation campaign against meningococcal serogroup C disease in the UK: a success story.

The introduction of meningococcal C conjugate (MCC) vaccine in the UK in November 1999 as a routine 3 dose infant immunisation course, with a single catch-up dose for all children aged between 12 months and 17 years, was the result of an intensive 5 year collaborative research programme funded by the Department of Health for England and involving public bodies, academia and vaccine manufacturers. The research programme established the safety and immunogenicity of MCC vaccines in infants, toddlers, pre-school and school-aged children. The nature and frequency of common adverse events in school-aged children was similar to that after a booster dose of diphtheria and tetanus vaccine given to the same age groups. The recommendation that a single dose was adequate for children aged 12 months and above was based on antibody levels measured by serum bactericidal assay and evidence of induction of immunological memory as shown by maturation of antibody avidity. Licensure by the Medicines Control Agency was based on serological criteria alone without direct evidence of efficacy and has set a precedent for other meningococcal conjugate polysaccharide vaccines. Vaccine coverage of around 85% was achieved in the targeted age groups and has resulted in a drop in the incidence of serogroup C disease in these groups of over 80% within 18 months of the start of the vaccination programme. Early post-licensure efficacy estimates for toddlers and teenagers (88 and 96%, respectively, in the first 16 months after vaccination) validate the serological criteria used for licensure. Surveillance of the prevalent serogroups and serosubtypes among invasive case isolates has shown no evidence of any capsular switching to serogroup B during the first 18 months of the MCC vaccination programme.

Humans↗

Safety, efficacy, and immunogenicity of a recombinant Osp subunit canine Lyme disease vaccine.

A subunit canine Lyme disease vaccine formulated with recombinant lipidated Osp A and OspB and saponin QS21 was assessed for safety, protective efficacy, and immunogenicity. Ten normal beagles were subcutaneously vaccinated twice at age 12 and 16 weeks, respectively. Three months after the second vaccination, the vaccinates and another 10 nonvaccinated control beagles were challenged by feeding ticks on each dog for 5 days using eight field-collected adult female and six adult male Ixodes scapularis infected with Lyme disease spirochetes per dog. Adverse reactions associated with the vaccinations were limited to injection site swellings which occurred within the first 48 h and resolved within a week. The local reaction was independent of vaccination times and tick challenge. On the basis of typical clinical signs, xenodiagnosis, and diagnostic immunoblotting, all 10 controls were infected; five developed lameness and three of them experienced at least two to three episodes of limping during a 10-month monitoring period. In contrast, eight of ten vaccinates were protected and two infected vaccinates, as judged by xenodiagnosis, were asymptomatic. None of the protected vaccinates developed antibodies to diagnostic spirochetal antigens other than OspA and OspB. In contrast, most controls produced antibodies to borrelial antigens, but not to OspA and OspB. Antibody production in vaccinates receiving a third vaccination 10 months postchallenge was greatly boosted; the geometric mean antibody titer was significantly higher (P < 0.0001) than that tested prechallenge. Thus, the subunit canine Lyme disease vaccine was safe and protective and elicited immunological memory. Vaccinated dogs were serologically distinguishable from those naturally exposed.

Animals↗

Immune response to tissue culture rabies vaccine in subjects who had previous postexposure treatment with Semple or suckling mouse brain vaccine.

Nerve tissue derived Semple and suckling mouse brain rabies vaccines are still widely used. Patients who experience a new rabies exposure and who were given such vaccines decades earlier are not uncommon in rabies endemic countries. The World Health Organization recommends that persons who have had a previous course of a potent tissue or avian culture rabies vaccine and are reexposed, be given booster infections on days 0 and 3 without rabies immune globulin. Persons who have had previous pre- or postexposure vaccination with a vaccine of unproven potency, should receive a full course of tissue or avian cell vaccine and immune globulin in the event of a new exposure. This study evaluated the immune response in 98 Thai patients who gave a history of rabies postexposure treatment with Semple or suckling mouse brain vaccines 10-50 years previously. The majority (81) had an anamnestic response and developed neutralizing antibodies that were above the recommended minimal acceptable level (0.5 IU ml-1) on day 7. This suggests that they still had immunological memory. A minority of 18% had antibody titers below this level on day 7. However, they all developed titers above 0.5 IU ml-1 on days 14 and 30. Failure to have an accelerated response to revaccination by day 7 did not appear to be related to age or time elapsed since previous nerve tissue derived vaccine administration. It was not possible to predict which subject will or will not have an acceptable level of antibody before day 14. Rabies exposed patients who give a prior history of vaccination with an unknown or nerve tissue derived vaccine should therefore be treated as if they had never been vaccinated.

Adolescent↗

Persistence of anti-HBs in children vaccinated against viral hepatitis B in the first year of life: follow-up at 5 and 10 years.

The persistence of anti-HBs protective levels in groups of children who had been immunized against Hepatitis B 5 and 10 years earlier, in their first year of life, has been studied. The results were analyzed according to the type of vaccine (both plasma-derived and DNA recombinant) and the number of doses administered (three or four doses). In addition, the protective effect of the vaccine in vaccinated subjects was studied in relation to the anti-HBc presence. The serologic results suggest that, in cohorts of children vaccinated 5 years earlier, a higher prevalence of subjects with anti-HBs protective levels was found, when the DNA recombinant vaccines were administered (97.6% for MSD Recombivax and 97.1% for SKF Engerix B); a lower one when the plasma-derived vaccine was used (80.4% Pasteur Merieux, Hevac B). Moreover, in cohorts of children vaccinated with plasma derived vaccine (hevac B) 10 years earlier, a higher prevalence of subjects with anti-HBs protective levels was demonstrated when four doses were administered (76.9%); a lower one when three doses were inoculated (57.5%). The absence of core antibody (anti-HBc) in responders to the vaccination shows the protective efficacy of both the DNA recombinant and plasma derived vaccines. On the other hand the presence of anti-HBc in some anti-HBs negative non-responders subjects shows the susceptibility of these people to infection. In anti-HBs negative vaccinated subjects the appearance of levels of anti-HBs in 95.9% of subjects, 1 week after the administration of a booster dose, demonstrates the presence of a solid immunologic memory.

Child↗

Ten-year follow-up study of neonatal hepatitis B immunization: are booster injections indicated?

One hundred and fourteen children, born to HBsAg-positive mothers received in the first year of life passive active prophylaxis for hepatitis B virus (HBV). They have been followed up to 10 years. A booster dose given in a cohort at the 5th year does not seem to increase protection against HBV. No difference in immunological memory was present at the 10th year between the group of children who had received the booster dose at 5 years of age and the group who did not.

Child↗

Immune response to an intercalated enhanced inactivated polio vaccine/oral polio vaccine programme in Israel: impact on the control of poliomyelitis.

A combined enhanced inactivated polio vaccine (EIPV) and oral polio vaccine (OPV) programme was introduced in Israel in 1990, with the purpose of providing a solution to the persistent polio morbidity in spite of a 30 year long OPV programme. The schedule comprised two doses of EIPV administered at the age of 2 and 4 months, intercalated with two doses of OPV at 4 and 6 months, followed by a reinforcing dose with the two vaccines simultaneously administered at 12 months. The 5-year evaluation of the programme included: the assessment of clinical suspicions of polio, early immune response in successive cohorts administered the new schedule, dynamics of the immune profile in a cohort followed up to the age of 5, and monitoring of wild poliovirus excretion in sewage specimens collected in 25 permanent sites throughout Israel as well as from the Palestinian Authority. No paralytic polio cases associated with a wild or vaccinal poliovirus strain were detected since the introduction of the programme. At the age of 4 months, one week after administration of the second EIPV and first OPV dose, 100% seropositivity and high geometric mean titres (GMTs) of neutralizing antibody (NA) to the three vaccinal and to the wild poliovirus type 1, responsible for the 1988 polio outbreak, were observed. No change in percent of seropositivity occurred between the age of 6 and 12 months. Thirty days after the IPV and OPV reinforcing doses, GMTs to each of the four poliovirus strains were > or = 3037. Up to the age of 5, the seropositivity was unchanged. After a 2.5-10-fold decline in the first year following the completion of the programme, GMTs to the three vaccinal and the wild poliovirus strain levelled off at rather high values, considered protective. Between 1990 and 1995, 16 wild poliovirus type 1 strains were isolated in three separate episodes in Gaza Strip sewage and once only in one Israeli site very close to Gaza City. The rapidly established, high and persistent NA titre to the vaccinal and wild poliovirus strains and the presence of immunological memory are indicative of high individual protection throughout the first 5 years of life. The only one-time introduction, without circulation, of a wild poliovirus strain in a single Israeli settlement suggests community protection. The intercalated programme offers a contribution to polio eradication by providing a solution to the primary and secondary failure associated with OPV, as well as to the control of vaccine-associated paralytic poliomyelitis.

Antibodies, Viral↗

Early immunization with conjugate vaccines.

Conjugate vaccines have been used during the neonatal period or in early infancy in order to test their safety and immunologic behaviour. Adverse events even in neonates and premature babies have been mild and spontaneously resolving. Anticapsular antibody concentrations after first doses of Hib conjugates in early infancy are generally low, but analysis of responses clearly demonstrates active antibody production. Concentrations after the whole primary series are at or close to the level achieved in routine vaccination programmes. Noteworthy, immunologic memory seems to be induced already by first doses during newborn period. These data suggest that protection against invasive Hib infections may be achieved early in life.

Bacterial Capsules↗

Immune response to revaccination with meningococcal A and C polysaccharides in Gambian children following repeated immunisation during early childhood.

Forty-two Gambian children randomised to receive two doses of meningococcal A/C polysaccharide vaccine (MPS) in infancy and either MPS (n = 15), meningococcal A/C conjugate (n = 13) or inactivated polio vaccine (IPV n = 14) at 2 years, were revaccinated with MPS at 5 years of age along with 39 matched control children. Meningococcal A and C polysaccharide antibodies were analysed by ELISA and bactericidal assay (SBA) in sera taken before and 10 days after revaccination. The geometric mean group SBA titre in the MPS group following revaccination was about half that of the unvaccinated controls (0.51 95%CI: 0.28, 0.90) for group A and less than half that of the controls for group C (0.41, 95%CI: 0.16, 1.03 P = 0.06). The group C SBA response in the conjugate group was 14-fold higher than in the MPS group (P < 0.001). Multiple doses of meningococcal polysaccharide in childhood may therefore attenuate the SBA response to both group A and group C polysaccharides. In contrast, vaccination with meningococcal A/C conjugate after MPS in infancy gives immunological memory to N. meningitidis group C.

Antibodies, Bacterial↗

Selection of an immunogenic peptide mimic of the capsular polysaccharide of Neisseria meningitidis serogroup A using a peptide display library.

The presently available meningococcal vaccine is poorly immunogenic in infants and fails to induce long-lasting immunity in adults. Efforts to convert this TI-2 type vaccine into a T dependent vaccine are being actively pursued and include conjugate vaccine development. Alternatively, the meningococcal polysaccharide can be rendered into a T dependent antigen through the use of peptides which mimic the capsular polysaccharide complexed or conjugated to potent protein carrier molecules. We have previously developed an anti-idiotypic monoclonal antibody (mAb) based peptide mimic of meningococcal group C polysaccharide (MCPS). A direct approach to identification of peptide mimics of antigen is through the use of peptide display libraries. We have utilized a phage library and a mAb with specificity for meningococcal group A polysaccharide (MAPS) to screen for a peptide mimic of MAPS. Six different peptide motifs were selected with the use of the mAb. Thirty-eight of the 60 sequenced phage clones were represented by motif 1 and 2 which differed only in three amino acids at the carboxy terminus. Immunological assays were performed. Phage clones with motif 1 and 2 were capable of binding human hyperimmune sera and inhibiting the binding of human hyperimmune sera to nominal antigen. Immunization with motif 1 peptide complexed to proteosomes resulted in an anti-MAPS antibody response. Priming with the peptide proteosome complex induced an anamnestic response indicating the formation of immunological memory.

Amino Acid Sequence↗

Persistence of immunity of Nematodirus battus infection in lambs.

Fifty-four Greyface Suffolk lambs aged 3 months were allocated to six groups of seven and one group of 12. Three groups were infected continuously with Nematodirus battus larvae (L3) over a 7-week period and three groups remained worm-free. One week after the last larval dose all six groups were treated with anthelmintic and challenged with a single dose of 30,000 N. battus L3 either 1, 6 or 12 weeks post-treatment (PT) and killed 10 days later. A seventh continuously infected and treated group (n = 12) was segregated into four sub-groups of three lambs which were used as tissue cell count controls and provided data on local cellular responses prior to challenge. Lambs in the first sub-group were killed immediately after anthelmintic treatment and those in the other sub-groups were killed on the same day that the lambs in the other main groups were challenged. Overall post-challenge worm burdens did not differ significantly between previously infected and challenge control groups although they were significantly reduced in both treatment groups by Week 12 PT. The principal manifestation of acquired immunity that was maintained throughout 12 weeks without further infection was retardation in larval development. There was also evidence of preferential rejection of male worms from immune lambs. Local mast cell, but not eosinophil, responses were significantly enhanced by previous infection and persisted up to Week 12 PT. The numbers of bone marrow eosinophils were significantly increased as a result of previous infection and this response persisted up to Week 12 PT. During primary infection anti-L4 and anti-adult worm IgG responses were significantly increased in the previously infected lambs by Day 42 post-infection. Eosinophil responses during this period did not differ between groups. The inflammatory cell responses, coupled with the parasitological observations, suggest that immunity to previous infection is maintained for up to 12 weeks PT without further antigenic stimulation. This 'immunological memory' may have waned partially after 6 weeks PT although the superimposition of age resistance may have masked the effect.

Animals↗

Observations on the proposed relationship between infection burden and early malignancy in developing countries (e.g., India).

Sastry and Parikh [Med. Hypotheses 60(4) (2003) 573] have recently sought an explanation for the fact that the occurrence of a particular cancer in populations in a developing country such as India takes place at a younger age (about one decade) than in populations in Western countries. They have hypothesized that a higher infectious burden in India gives rise to repeated cell divisions leading to early senescence of immune cells, and, thence their reduced ability for immune surveillance against cancer, resulting in earlier onset of cancer. The analysis presented here points out to some difficulties with this interpretation, both on empirical and theoretical grounds. The reduced surveillance ability, caused by higher infectious burden, of the immune cells postulated by Sastry and Parikh [loc. cit.] would also mean that populations in India should suffer higher incidence of cancer, as compared to people in Western countries; the empirical data show that, in fact, quite the opposite is true - in the present communication shows that for many common cancers, typical cities in India show the lowest incidence. Theoretically, it is postulated here that repeated heavy infections in India, in fact, challenge the immune system, particularly the adaptive immune system and create an immunological memory: this trains and strengthens the immune system against the future battles. Also it is shown that the shortening of the telomeric cap by repeated cell divisions caused by heavy infectious attacks, as argued by Sastry and Parikh [loc. cit.], is not the cause of earlier onset of cancers among Indians; in fact, when telomeric caps become shortened to a critical point, a danger signal is generated arresting the cell cycle - thus, it provides a fundamental mechanism for ordering the cell to cease proliferation. It is suggested that the root of occurrence of cancers at an earlier age in India perhaps lies in the accumulation of mutations at an earlier age among Indians who do develop cancers; the factors responsible for these accelerated mutations are not clear at the present time and need further investigation.

Age Distribution↗

Alphavirus expression vectors and their use as recombinant vaccines: a minireview.

Alphavirus vectors have become widely used in basic research to study the structure and function of proteins and for protein production purposes. Development of a variety of vectors has made it possible to deliver foreign sequences as naked RNA or DNA, or as suicide virus particles produced using helper vector strategies. Preliminary reports also suggest that these vectors may be useful for in vivo applications where transient, high-level protein expression is desired, such as recombinant vaccines. The initial studies have already shown that alphavirus vaccines can induce strong humoral and cellular immune responses with good immunological memory and protective effects.

Alphavirus↗

Pilus ELISA and an anamnestic test for the diagnosis of virulent ovine footrot and its application in a disease control program in Nepal.

The immunological memory (anamnestic) responses in sheep recovered from virulent footrot (VFR) can be aroused by subcutaneous injection of outer membrane protein (OMP) antigens of Dichelobacter nodosus. The magnitude of this response is directly correlated to the highest antibody response attained during infection and memory lasts at least a year after recovery from VFR. However, some older animals show non-specific responses to OMP antigens. In this study an evaluation of D. nodosus pilus antigen for the anamnestic diagnosis of footrot in sheep was undertaken. The results indicated that the primary and anamnestic responses to pilus were similar in character to OMP antigen but were highly specific. The sensitivity of the procedure for detection of sheep with a history of VFR was approximately 80%. A low proportion of sheep with mild lesions due to virulent strains of D. nodosus reacted to anamnestic challenge. Anamnestic challenge with 10 microg pilus was used in a VFR surveillance program in migratory sheep flocks in Nepal. Conventional diagnostic methods could not be applied during the disease transmission periods in these flocks because of their migration to alpine pastures far away from human habitation. The results supported clinical and bacteriological findings suggesting that virulent strains of D. nodosus have apparently been eliminated from these flocks in Nepal.

Animals↗

Increased litter survival rates, reduced clinical illness and better lactogenic immunity against TGEV in gilts that were primed as neonates with porcine respiratory coronavirus (PRCV).

Establishing immunological memory in female piglets at a young age with PRCV was effective in inducing a secondary immune response to a limiting dose of virulent TGEV given orally 13-18 days prior to farrowing. Subsequently, because of passive antibody transfer, the offspring of these primed gilts were more efficient in surviving a lethal TGEV challenge. An average survival rate of 89% occurred in 6 litters of piglets from primed gilts that were boosted with 2.8 x 10(6) plaque forming units (PFU) of TGEV whereas 76% of the piglets survived in three litters that suckled primed gilts boosted with 3.0 x 10(5)PFU of TGEV. Non-primed gilts given identical pre-farrowing doses of TGEV had litter survival rates of 63 and 55%, respectively. Moreover, both groups of litters from primed gilts suffered less clinical illness (as measured by the extent of weight loss post-challenge) than control litters. Priming of the piglets as neonates and boosting the pregnant gilts produced an anamnestic systemic immune response and correspondingly higher milk titers in the primed gilts compared to control animals. Thus, priming piglets with PRCV was beneficial in providing resistance to TGEV and could be incorporated into a vaccine strategy that yields better protection against TGEV.

Animals↗

Vaccination against the major infectious diseases.

The reputation of vaccination rests on a 200-year-old history of success against major infectious diseases. That success has led to the doctrine of 'for each disease, a vaccine'. Although some diseases have proved frustrating, this doctrine carries considerable truth. However, when one reviews the vaccines now available it is apparent that most successes have been obtained when the microbe has a bacteremic or viremic phase during which it is susceptible to the action of neutralizing antibodies, and before replication in the particular organ to which it is tropic. Poliomyelitis and infections by capsulated bacteria are examples where vaccination has worked efficiently. However, some success has also been achieved against agents replicating on respiratory or gastrointestinal mucosae. Influenza, pertussis and rotavirus vaccines are examples of such agents, against which it has been possible to induce immune responses acting locally as well as systemically. In addition, when bacteria produce disease through exotoxins, purification and chemical or genetic inactivation of those toxins has yielded highly efficacious vaccines. Control of intracellular pathogens has not been achieved, except partly with the BCG vaccine against tuberculosis, and modern efforts are directed towards pathogens against which cellular immune responses are critical. In general, two achievements have been crucial to the success of vaccines: the induction of long-lasting immunological memory in individuals and the stimulation of a herd immunity that enhances control of infectious diseases in populations.

Animals↗

Anti-HBs responses in children vaccinated with different schedules of either plasma-derived or HBV DNA recombinant vaccine.

This study evaluated the immunogenic and protective effects of plasma-derived and DNA recombinant anti-hepatitis B virus vaccines administered to infants at various ages and with different vaccination schedules: 3 monthly doses in the first 3 months of life, 3 doses (at 3, 5 and 11 months) or 2 doses (at 1 and 3 months) or 2 doses (at 3 and 5 months). Anti-HBs (hepatitis B surface) and anti-HBc (hepatitis B core) markers were investigated twice: one month and ten years after vaccination in 261 children immunized with plasma-derived vaccine, and one month and five years after vaccination in 449 children immunized with DNA recombinant vaccine. In all groups, the appearance of anti-HBs protective levels one month after vaccination and their persistence in the following years were found in a larger number of subjects when the vaccine doses had been administered after the third month of life rather than in the first three months. Moreover, our results show that the reappearance of surface antibodies a week after the booster, in vaccinated children who became anti-HBs- in the years following vaccination, occurred in a larger number of subjects when the primary vaccination with 3 doses had been performed in the first quarter or with 2 or 3 doses in the second quarter. In contrast, protective levels of anti-HBs were found in a small number of children belonging to the group vaccinated with 2 doses in the first three months, and among them the majority seroconverted only one month after the booster. Anti-HBc was found 10 years after vaccination in only one child immunized with 2 doses of plasma-derived vaccine, and 5 years after vaccination in two children immunized with 2 doses of DNA recombinant vaccine. All these children were found to lose anti-HBs, and none of them had signs of disease or became a carrier. Based on these results, the disappearance, in some children, of protective levels of anti-HBs in the years following vaccination does not mean the loss of anti-HBV protection. In fact, the trial showed that they reacted immediately to booster stimulation, demonstrating a solid immunologic memory. Therefore, there may be no reason for giving booster injections when the vaccination of infants is carried out correctly.

Female↗