Systematic review of mucosal immunity induced by oral and inactivated poliovirus vaccines against virus shedding following oral poliovirus challenge.

Inactivated poliovirus vaccine (IPV) may be used in mass vaccination campaigns during the final stages of polio eradication. It is also likely to be adopted by many countries following the coordinated global cessation of vaccination with oral poliovirus vaccine (OPV) after eradication. The success of IPV in the control of poliomyelitis outbreaks will depend on the degree of nasopharyngeal and intestinal mucosal immunity induced against poliovirus infection. We performed a systematic review of studies published through May 2011 that recorded the prevalence of poliovirus shedding in stool samples or nasopharyngeal secretions collected 5-30 days after a "challenge" dose of OPV. Studies were combined in a meta-analysis of the odds of shedding among children vaccinated according to IPV, OPV, and combination schedules. We identified 31 studies of shedding in stool and four in nasopharyngeal samples that met the inclusion criteria. Individuals vaccinated with OPV were protected against infection and shedding of poliovirus in stool samples collected after challenge compared with unvaccinated individuals (summary odds ratio [OR] for shedding 0.13 (95% confidence interval [CI] 0.08-0.24)). In contrast, IPV provided no protection against shedding compared with unvaccinated individuals (summary OR 0.81 [95% CI 0.59-1.11]) or when given in addition to OPV, compared with individuals given OPV alone (summary OR 1.14 [95% CI 0.82-1.58]). There were insufficient studies of nasopharyngeal shedding to draw a conclusion. IPV does not induce sufficient intestinal mucosal immunity to reduce the prevalence of fecal poliovirus shedding after challenge, although there was some evidence that it can reduce the quantity of virus shed. The impact of IPV on poliovirus transmission in countries where fecal-oral spread is common is unknown but is likely to be limited compared with OPV.

Safety of pentavalent DTaP-IPV/Hib combination vaccine in post-marketing surveillance in Guangzhou, China, from 2011 to 2017.

BACKGROUND: The DTaP-IPV/Hib combination vaccine can replace the acellular tetanus vaccine, polio vaccine, and the Haemophilus influenzae type B vaccine. Data on the safety of DTaP-IPV/Hib vaccines are required. We aimed to evaluate the safety of the vaccination program. METHODS: Using the National Adverse Events Following Immunization (AEFI) surveillance system (CNAEFIS) in Guangzhou, China, a retrospective study was performed from May 11, 2011, to December 31, 2017. There were 376 cases of adverse events after vaccination with the DTaP IPV/Hib vaccine. The primary analysis indicators were the number of vaccines used, the number of AEFI reports received, and the reporting rate (per 100,000). RESULTS: From May 1, 2011, to December 31, 2017, 516,000 doses of vaccine were inoculated, and 376 cases of adverse reactions were reported; the reporting rate was 72.8 per 100,000 vaccines. There were eight cases of serious AEFIs (1.5 per 100,000), with four cases of thrombocytopenic purpura (0.8 per 100,000); three cases of cyanosis of the lips, stiffness, and flexion of limbs, and convulsions (0.6 per 100,000); and one case of a high fever (0.2 per 100,000). The highest incidence of AEFIs occurred after the fourth dose (n = 207, 55.0%, 40.1 per 100,000), followed by the first dose (n = 81, 21.5%, 15.7 per 100,000), second dose (n = 48, 12.8%, 9.3 per 100,000) and third dose (n = 40, 10.6%, 7.7 per 100,000). The AEFI incidence was higher after injection of the vaccine into the deltoid muscle of the upper arm (n = 276, 73.4%, 53.5 per 100,000) than after injection of the vaccine into the thigh (n = 100, 26.6%, 19.4 per 100,000). There was a significant difference between AEFIs after injection into the deltoid of the upper arm deltoid and the thigh (x2 = 164.8, P < 0.05). CONCLUSIONS: Most of the reported AEFIs after DTaP-IPV/Hib vaccination are not serious. There were four cases of TP in this study; vaccination may be a rare cause of thrombocytopenic purpura.

DTaP-IPV-HepB-Hib Vaccine (Hexyon®): An Updated Review of its Use in Primary and Booster Vaccination.

Hexyon® is a fully-liquid, ready-to-use, hexavalent vaccine approved in the EU since 2013 for primary and booster vaccination in infants and toddlers from age 6 weeks against diphtheria, tetanus, pertussis, hepatitis B (HB), poliomyelitis, and invasive diseases caused by Haemophilus influenzae type b (Hib). While the source of HB antigen in Hexyon® is different from other vaccines, the rest of its valences have been extensively used in other approved vaccines. Hexyon® is highly immunogenic for all its component toxoids/antigens when used as primary and booster vaccine in infants and toddlers, irrespective of vaccination schedule. It provides durable protection against hepatitis B. Hexyon® can be used for a mixed primary series of hexavalent-pentavalent-hexavalent vaccines or as a booster in infants primed with Infanrix hexa™ or pentavalent (whole-cell or acellular pertussis) vaccines. Coadministration of Hexyon® with other common childhood vaccines did not affect immune response to any vaccines. Hexyon® has a good reactogenicity/safety profile. The immunogenicity and safety profile of Hexyon® was similar to that of several approved vaccines, including Infanrix hexa™. However, Hexyon® offers the convenience of full-liquid, ready-to-use formulation, which may minimize vaccination errors and preparation time. Thus, Hexyon® is a convenient, useful option for vaccination against childhood diseases caused by six major pathogens.

Inactivated poliovirus type 2 vaccine delivered to rat skin via high density microprojection array elicits potent neutralising antibody responses.

Polio eradication is progressing rapidly, and the live attenuated Sabin strains in the oral poliovirus vaccine (OPV) are being removed sequentially, starting with type 2 in April 2016. For risk mitigation, countries are introducing inactivated poliovirus vaccine (IPV) into routine vaccination programs. After April 2016, monovalent type 2 OPV will be available for type 2 outbreak control. Because the current IPV is not suitable for house-to-house vaccination campaigns (the intramuscular injections require health professionals), we developed a high-density microprojection array, the Nanopatch, delivered monovalent type 2 IPV (IPV2) vaccine to the skin. To assess the immunogenicity of the Nanopatch, we performed a dose-matched study in rats, comparing the immunogenicity of IPV2 delivered by intramuscular injection or Nanopatch immunisation. A single dose of 0.2 D-antigen units of IPV2 elicited protective levels of poliovirus antibodies in 100% of animals. However, animals receiving IPV2 by IM required at least 3 immunisations to reach the same neutralising antibody titres. This level of dose reduction (1/40th of a full dose) is unprecedented for poliovirus vaccine delivery. The ease of administration coupled with the dose reduction observed in this study points to the Nanopatch as a potential tool for facilitating inexpensive IPV for mass vaccination campaigns.

Antibody response and viral excretion after live polio vaccine or a combined schedule of live and inactivated polio vaccines.

A randomized controlled trial was performed in infants undergoing routine immunization in North Hertfordshire. Ninety-six children received a single dose of inactivated polio vaccine, followed by two doses of live attenuated oral polio vaccine and 97 children received three doses of live attenuated oral polio vaccine at 2, 3 and 4 months of age. Blood samples were taken by study nurses 6 weeks after vaccination and stool samples were collected by parents weekly for 4 weeks after each dose of vaccine. Follow-up was completed for 92 of 96 (96%) children in the combined schedule group and 92 of 97 (95%) in the control group. After vaccination the proportions of children with detectable antibody to poliovirus serotypes 1, 2 and 3 were high and similar between groups and geometric mean titers (95% confidence interval) to poliovirus types 1, 2 and 3 were 264 (200 to 347), 375 (311 to 450) and 189 (144 to 250) in the combined schedule group and 369 (290 to 469), 401 (321 to 498) and 206 (145 to 293) in the live vaccine group, respectively. The only significant difference between groups in rates of viral excretion was observed after the second dose of live attenuated oral polio vaccine, when excretion of type 3 poliovirus was reduced in those children who had received prior inactivated polio vaccine (P = 0.05). This study suggests that, compared with the current schedule, a combined schedule of inactivated and live poliovaccines is likely to produce equivalent individual protection against poliomyelitis and is unlikely to substantially alter circulation of poliovirus in the community.(ABSTRACT TRUNCATED AT 250 WORDS)

Antipolio prophylaxis of immunocompromised children during a nationwide oral poliovaccine campaign.

A nationwide vaccination campaign with oral poliovirus vaccine was organized in Finland in 1985 to halt an outbreak of poliomyelitis. Immunocompromised persons and their household contacts were excluded from the oral poliovirus vaccine target group and given instead a dose of inactivated poliovirus vaccine. This gave us an opportunity to determine whether immunocompromised persons are protected from poliomyelitis during an outbreak and oral poliovirus campaign. Fourteen children, ages 3 to 17 years, with leukemia were given a booster dose of a novel high antigen content, trivalent inactivated poliovirus vaccine. All but two responded by an at least 4-fold increase in serum-neutralizing antibodies to at least one poliovirus serotype. These results indicate that children with acute lymphocytic leukemia in remission respond well to a booster dose of inactivated poliovirus vaccine. Antibody concentrations to the uncommon local epidemic strain of type 3 poliovirus remained, however, relatively low in most patients (median, 1:6) suggesting relatively impaired heterologous response to vaccination. Possible spread of live vaccine viruses to the inactivated poliovirus-vaccinated children and their close contacts was evaluated by examining weekly fecal specimens from 20 children and their 19 regular adult contacts for cytopathic viruses. No polioviruses were isolated from 224 specimens examined, indicating that this high risk population was well-protected from unintended exposure to live polioviruses.

The effect of prophylaxis with chloroquine and proguanil on delayed-type hypersensitivity and antibody production following vaccination with diphtheria, tetanus, polio, and pneumococcal vaccines.

In vitro studies have shown that anti-malarial drugs suppress immunity. In this study, the effects of chloroquine and proguanil (Paludrine) on the cellular and humoral immune system were measured by two in vivo methods: 1) cell-mediated immunity (delayed cutaneous hypersensitivity) i.e., skin tests with seven delayed-type common antigens (Multitest) and 2) humoral immunity by measurement of specific antibody response to vaccination. Sixty healthy young individuals were randomized into four groups and given 1) no treatment (controls), 2) chloroquine diphosphate (500 mg/week), 3) chloroquine diphosphate (1,000 mg/week), or 4) proguanil hydrochloride (200 mg/day) for six weeks. Skin testing was performed on days 0 and 28. Vaccinations with diphtheria, tetanus, polio, and pneumococcal polysaccharide antigen vaccines were performed on day 28, and the presence of specific antibodies was determined on days 0, 28, and 42. The skin tests induced a significant increase in skin reactive areas from day 0 to day 28 in all groups. Furthermore, the skin test induced an increase in the level of specific IgG for diphtheria and tetanus, but had no effect on antibodies to antigens not included in the skin test. The results showed that there were no significant differences among the four groups regarding skin test areas and increases in antibody titers following vaccination. Therefore, it is concluded that in healthy persons, six weeks intake of chloroquine, even in double doses, or proguanil in chemoprophylactic dosages, does not induce any detectable suppression of delayed-type hypersensitivity or vaccination responses to diphtheria, tetanus, polio, or pneumococcal polysaccharide antigens.

Deterministic models for the eradication of poliomyelitis: vaccination with the inactivated (IPV) and attenuated (OPV) polio virus vaccine.

Currently two polio vaccines, IPV and OPV, are in use which differ markedly in their epidemiological parameters. A simple epidemiological model in terms of ordinary differential equations is proposed to study the effects of vaccination campaigns using these vaccines. The numbers of interest are the reproduction number of the disease in the presence of vaccination and the critical vaccination coverage necessary to prevent an outbreak. For these numbers explicit representations are determined which can be used in comparing different vaccination strategies.

Influence of several bacterial and viral vaccines on hepatic drug metabolism in mice.

Pentobarbital-induced sleeping time was found to be significantly prolonged in mice within at least 4 days following either whooping cough, tetanus, rubella or poliomyelitis vaccination. By contrast, barbital-induced sleeping time remained unaffected, These findings provide further evidence of a correlation between inhibition of liver drug metabolizing enzymes and stimulation of the immune response.

Effect of inactivated viral vaccines (human) on frequency of micronuclei in bone marrow erythrocytes of mice.

Cytogenetic effects of the two inactivated viral vaccines (polio and antirabies) were studied in adult male mice by the micronucleus test. Polio salk vaccine did not induce micronuclei formation at both human (0.5 ml) and 1/5th human doses. Antirabies vaccine induced micronuclei in poly and total erythrocytes only at human dose of 2 ml. Beta-propiolactone (BPL) induced micronuclei at higher dose of 5.7 mg, but not at 0.57 mg (approximate concentration present in 2 ml of rabies vaccine). The P/N ratio was not affected in vaccinated and BPL inoculated animals. Antirabies vaccine induced micronuclei percentage was more than the BPL value.

[Effect of viral vaccines on animal bone marrow cell chromosomes]. / Issledovanie vliianiia protivovirusnykh vaktsin na khromosomy kletok kostnogo mozga zhivotnykh

A comparative study on the effect of a number of viral vaccines (live and inactivated vaccinia, poliovirus type II, measles, rabies vaccines) on chromosomes of mouse bone marrow cells was carried out. Most vaccines were found to impair the process of first divisions of these cells after vaccination. Live vaccinia vaccine and live fixed rabies virus cause an increase in the rate of structural chromosome aberrations at later intervals, 30-90 days after immunization. The main type of chromosome disorders is chromatid break. Some of the live vaccines studied (poliovaccine type II, measles vaccine) and inactivated vaccines caused no increase in the rate of cromosome structure disorders as compared to the control. Live fixed rabies virus exerts a stronger impairing effect on division of mouse bone marrow cells than a rabies vaccine with residual virulence. A rabies vaccine completely inactivated by UV-irradiation had no impairing effect on chromosomes of immunized animals. Thus, some live vaccines, unlike inactivated ones, cause chromosome disorders in bone marrow cells of mice late after immunization and, apparently, subsequent death of some cells with the most important distrubances.

[Induction of mutations in mammalian cells by the action of live vaccinal strains of poliomyelitis virus]. / Induktsiia mutatsii v kletkakh mlekopitaiushchikh pod deistviem zhivykh vaktsinal'nykh shtammov virusa poliomielita.

The attenuated strains' poliomyelitis virus induces mutagenesis in human and Chinese hamster cultured cells. The mutagenic action of the poliovirus is detected at chromosome and gene levels and directly depends on the multiplicity of cell infection. Possibilities for developing nonmutagenic antivirus vaccines are discussed.

[Study of the chromosomes in the bone marrow cells of mice inoculated subsequently with various vaccines]. / Issledovanie khromosom v kletkakh kostnogo kozga myshei, privitykh posledovatel'no razlichnymi vaktsinami

Studies in the effect of a complex of inoculating preparations (poliovaccine, APDD-vaccine, smallpox vaccine, measles vaccine) on dividing cells of bone marrow in mice in line CC57Br showed that a reduction of the interval between introduction of vaccines different in the antigenic respect from 14 days to 4 days results in an increase in frequency of structural chromosomal aberrations 1-2 months after the whole course of inoculations.

Next generation inactivated polio vaccine manufacturing to support post polio-eradication biosafety goals.

Worldwide efforts to eradicate polio caused a tipping point in polio vaccination strategies. A switch from the oral polio vaccine, which can cause circulating and virulent vaccine derived polioviruses, to inactivated polio vaccines (IPV) is scheduled. Moreover, a manufacturing process, using attenuated virus strains instead of wild-type polioviruses, is demanded to enhance worldwide production of IPV, especially in low- and middle income countries. Therefore, development of an IPV from attenuated (Sabin) poliovirus strains (sIPV) was pursued. Starting from the current IPV production process based on wild type Salk strains, adaptations, such as lower virus cultivation temperature, were implemented. sIPV was produced at industrial scale followed by formulation of both plain and aluminium adjuvanted sIPV. The final products met the quality criteria, were immunogenic in rats, showed no toxicity in rabbits and could be released for testing in the clinic. Concluding, sIPV was developed to manufacturing scale. The technology can be transferred worldwide to support post polio-eradication biosafety goals.

Spotlight on DTPa-HBV-IPV/Hib Vaccine (Infanrix hexa).

Infanrix hexa, administered intramuscularly, is a diphtheria, tetanus, acellular pertussis, hepatitis B (HBV), inactivated poliomyelitis and Haemophilus influenzae type b (Hib) conjugate vaccine, indicated for primary and booster vaccination of infants. Infanrix hexa should be administered as a two- or three-dose primary vaccination course in infants aged < or =6 months, followed by booster vaccination between 11 and 18 months of age, with an interval of at least 6 months between the last dose of primary vaccination and the booster dose. This spotlight reviews the immunogenicity and protective effectiveness, as well as the reactogenicity and safety of Infanrix hexa. Infanrix hexa as primary and booster vaccination was safe and highly immunogenic for all its component toxoids/antigens in infants aged <2 years, regardless of vaccination schedules. Its immunogenicity and safety profiles were generally similar to those of currently available vaccines, the diphtheria, tetanus and acellular pertussis-based pentavalent vaccines plus monovalent HBV or Hib vaccines. In large clinical studies, Infanrix hexa elicited a strong immune response against vaccine toxoids/antigens, as indicated by high seroprotection/seropositivity/vaccine response rates and geometric mean titers. Moreover, antibodies against vaccine toxoids/antigens persisted for up to a mean of approximately 6 years after booster vaccination, and the vaccine induced long-term immune memory against hepatitis B surface antigen and Hib antigen. A strong immune response against Infanrix hexa toxoids/antigens after primary vaccination was also induced in infants who had received a dose of HBV vaccine at birth and in pre-term infants, although the response in the latter group was somewhat lower than that in full-term infants. In addition, when coadministered with other childhood vaccines, the immunogenicity of Infanrix hexa or that of the concomitantly administered vaccine was generally not altered. Hexavalent vaccines, including Infanrix hexa, were protective against invasive Hib disease; Infanrix hexa is also expected to be protective against pertussis. Most solicited local and general symptoms with Infanrix hexa were mild to moderate in intensity and the vaccine was associated with few unsolicited adverse events. Available clinical data from more than 10 years' experience with the vaccine suggest that Infanrix hexa as primary and booster vaccination is a safe and useful option for providing protection against the common childhood diseases of diphtheria, tetanus, poliomyelitis, pertussis, hepatitis B and invasive Hib disease.

The evaluation of a physical method for the quantification of inactivated poliovirus particles and its relationship to D-antigenicity and potency testing in rats.

The use of a density gradient procedure for the quantification of intact, inactivated poliovirus particles in vaccine preparations is described. The procedure is both sensitive and highly reproducible and the results correlate with those of potency tests in rats and with D-antigen content as measured by ELISA. Because of the occasional ambiguity observed with D-antigen assays, it is suggested that the density gradient procedure will provide valuable additional information for the in vitro assessment of inactivated poliovirus preparations.