Safety,tolerability, and immunogenicity of inactivated poliovirus vaccine with or without E.coli double mutant heat-labile toxin (dmLT) adjuvant in healthy adults; a phase 1 randomized study

BackgroundInactivated trivalent poliovirus vaccine (IPV) induces humoral immunity, which protects against paralytic poliomyelitis but does not induce sufficient mucosal immunity to block intestinal infection. We assessed the intestinal immunity in healthy adults in Belgium conferred by a co-formulation of IPV with the mucosal adjuvant double mutant Labile Toxin (dmLT) derived from Escherichia coli.MethodsHealthy fully IPV-vaccinated 18–45-year-olds were randomly allocated to three groups: on Day 1 two groups received one full dose of IPV (n = 30) or IPV + dmLT (n = 30) in a blinded manner, and the third received an open-label dose of bivalent live oral polio vaccine (bOPV types 1 and 3, n = 20). All groups received a challenge dose of bOPV on Day 29. Participants reported solicited and unsolicited adverse events (AE) using study diaries. Mucosal immune responses were measured by fecal neutralization and IgA on Days 29 and 43, with fecal shedding of challenge viruses measured for 28 days. Humoral responses were measured by serum neutralizing antibody (NAb).ResultsSolicited and unsolicited AEs were mainly mild-to-moderate and transient in all groups, with no meaningful differences in rates between groups. Fecal shedding of challenge viruses in both IPV groups exceeded that of the bOPV group but was not different between IPV and IPV + dmLT groups. High serum NAb responses were observed in both IPV groups, alongside modest levels of fecal neutralization and IgA.ConclusionsAddition of dmLT to IPV administered intramuscularly neither affected humoral nor intestinal immunity nor decreased fecal virus shedding following bOPV challenge. The tolerability of the dose of dmLT used in this study may allow higher doses to be investigated for impact on mucosal immunity.Registered on ClinicalTrials.gov - NCT04232943.     

The novel adjuvant dmLT promotes dose sparing,mucosal immunity and longevity of antibody responses to the inactivated polio vaccine in a murine model

One option for achieving global polio eradication is to replace the oral poliovirus vaccine (OPV), which has the risk of reversion to wild-type virulence, with the inactivated poliovirus vaccine (IPV) vaccine. Adjuvants and alternate routes of immunization are promising options that may reduce antigen dose in IPV vaccinations, potentially allowing dose sparing and cost savings. Use of adjuvants and alternate routes of immunization could also help promote mucosal immunity, potentially mimicking the protection against intestinal virus shedding seen with OPV. In the current study, we examined the impact of combining the novel adjuvant dmLT with trivalent IPV for dose sparing, induction of mucosal immunity and increasing longevity of anti-poliovirus (PV) responses in a mouse model following either intradermal (ID) or intramuscular (IM) delivery.We found that non-adjuvanted ID delivery was not superior to IM delivery for fractional dose sparing, but was associated with development of mucosal immunity. Vaccination with IPV + dmLT promoted serum anti-PV neutralizing antibodies with fractional IPV doses by either IM or ID delivery, achieving at least five-fold dose sparing above non-adjuvanted fractional doses. These responses were most noticeable with the PV1 component of the trivalent vaccine. dmLT also promoted germinal center formation and longevity of serum anti-PV neutralizing titers. Lastly, dmLT enhanced mucosal immunity, as defined by fecal and intestinal anti-PV IgA secretion, when included in IPV immunization by ID or IM delivery. These studies demonstrate that dmLT is an effective adjuvant for either IM or ID delivery of IPV. Inclusion of dmLT in IPV immunizations allows antigen dose sparing and enhances mucosal immunity and longevity of anti-PV responses.     

Effect of adjuvanting RBD-dimer-based subunit COVID-19 vaccines with Sepivac SWE™

Protein subunit vaccines have been widely used to combat infectious diseases, including the current COVID-19 pandemic. Adjuvants play the key role in shaping the quality and magnitude of the immune response to protein and inactivated vaccines. We previously developed a protein subunit COVID-19 vaccine, termed ZF2001, based on an aluminium hydroxide-adjuvanted tandem-repeat dimeric receptor-binding domain (RBD) of the viral spike (S) protein. Here, we described the use of a squalene-based oil-in-water adjuvant, Sepivac SWE™ (abbreviated to SWE), to further improve the immunogenicity of this RBD-dimer-based subunit vaccines. Compared with ZF2001, SWE adjuvant enhanced the antibody and CD4⁺ T-cell responses in mice with at least 10 fold of dose sparing compared with ZF2001 adjuvanted with aluminium hydroxide. SWE-adjuvanted vaccine protected mice against SARS-CoV-2 challenge. To ensure adequate protection against the currently circulating Omicron variant, we evaluated this adjuvant in combination with Delta-Omicron chimeric RBD-dimer. SWE significantly increased antibody responses compared with aluminium hydroxide adjuvant and afforded greater neutralization breadth. These data highlight the advantage of emulsion-based adjuvants to elevate the protective immune response of protein subunit COVID-19 vaccines.     

Immunogenicity and safety of an adjuvanted inactivated polio vaccine,IPV-Al,compared to standard IPV: A phase 3 observer-blinded,randomised, controlled trial in infants vaccinated at 6, 10, 14 weeks and 9 months of age

BackgroundA dose-sparing inactivated polio vaccine (IPV-Al), obtained by adsorption of inactivated virus to an aluminium hydroxide adjuvant, can help mitigate global supply and the cost constraints of IPV. The objective of this trial was to demonstrate the non-inferiority of IPV-Al to standard IPV.MethodsThis phase 3, observer-blinded, randomised, controlled trial was conducted at 5 investigational sites in the Philippines. Infants not previously vaccinated with any polio vaccines were randomised to receive three IPV-Al (n = 502) or IPV vaccinations (n = 500) at 6, 10 and 14 weeks of age plus a booster vaccination at 9 months. The primary endpoint was type-specific seroconversion, defined as an antibody titre ≥4-fold higher than the estimated maternal antibody titre and a titre ≥8, one month after the primary vaccination series.ResultsSeroconversion rates following primary vaccination with IPV-Al (483 infants in the per-protocol analysis set) or IPV (478 infants) were: polio type 1, 97.1% versus 99.0%; type 2, 94.2% versus 99.0%; and type 3, 98.3% versus 99.6%. IPV-Al was non-inferior to IPV, as the lower 95% confidence limits of the treatment differences were above the predefined −10%-point limit: type 1, −1.85% (−3.85; −0.05); type 2, −4.75% (−7.28; −2.52); type 3, −1.24 (−2.84; 0.13). The booster effect (geometric mean titre (GMT) post-booster / GMT pre-booster) was: type 1, 63 versus 43; type 2, 54 versus 47; type 3, 112 versus 80. IPV-Al was well tolerated with a safety profile comparable to that of IPV. Serious adverse events were recorded for 29 infants (5.8%, 37 events) in the IPV-Al group compared to 28 (5.6%, 48 events) in the IPV group.ConclusionNon-inferiority of IPV-Al to IPV with respect to seroconversion was confirmed and a robust booster response was demonstrated. Both vaccines had a similar safety profile.ClinicalTrials.gov identifier: NCT03032419.     

Persistence of protective anti-poliovirus antibody levels in 4-year-old children previously primed with Picovax®, a trivalent,aluminium-adjuvanted reduced dose inactivated polio vaccine

BackgroundTo meet the demand for effective and affordable inactivated polio vaccines (IPVs), a reduced dose, aluminium hydroxide (Al(OH)₃)-adjuvanted IPV vaccine was developed (IPV-Al, Picovax®) and evaluated in clinical trials. The present trial is an extension of two previous trials (a primary and a booster trial). The aim was to evaluate the persistence of seroprotective antibodies (poliovirus type-specific antibody titre ≥ 8) in 4-year-old children who previously received IPV–Al as primary and booster vaccine doses and to determine the potential booster response and safety profile of an additional dose of IPV-Al.MethodsChildren participating in the two previous trials were invited to receive one additional dose of IPV-Al at 4 years of age (2.5 years after the booster dose) and to have their blood samples collected to measure the pre- and post-vaccination antibody titres. Systemic adverse events (AEs) and local reactogenicity were recorded.ResultsAt study entry, the seroprotection rates were 89.2%, 100% and 91.1% against poliovirus type 1, 2 and 3, respectively. The additional vaccination with IPV-Al boosted the level of poliovirus type 1, 2 and 3 antibodies to above the seroprotection threshold for all but one subject, i.e., 99.4% for type 1 and 100% for types 2 and 3. The additional dose induced a robust booster response of a 26.3-, 13.9- and 30.9-fold increase in titre for poliovirus types 1, 2 and 3, respectively. The vaccine was well tolerated, with only mild and transient AEs reported.ConclusionsThe present trial demonstrated that the primary vaccination with an aluminium-adjuvanted reduced dose IPV induced a persistent immune memory as evidenced by the robust anamnestic response when the subjects were re-exposed to the antigen 2.5 years after the last dose. Thus, the IPV-Al is an efficient and safe addition to increase the availability of inactivated polio vaccines globally. (ClinicalTrials.gov reg no. NCT04448132).     

Antibody and T-cell responses to a virosomal adjuvanted H9N2 avian influenza vaccine: impact of distinct additional adjuvants

A highly efficacious vaccine is required to counteract a threat of an avian influenza pandemic. Increasing the potency of vaccines by adjuvation is essential not only to overcome generally low immunogenicity of pandemic strains, but also to allow dose sparing and as such to make it feasible to satisfy huge global production demands. In this study we evaluated the ability of four distinct adjuvants to further increase immune responses to a virosomal adjuvanted avian H9N2 influenza vaccine in mice. Currently registered adjuvants aluminium phosphate, aluminium hydroxide and MF59, as well as a novel promising adjuvant MATRIX-M were included in the study. Our results demonstrate that all adjuvants significantly increased the H9N2 haemagglutinin (HA) inhibition and ELISA antibody titers induced with the virosomal adjuvanted vaccine. The adjuvants exhibited different effect on the isotype of virus specific antibodies, with MATRIX-M inducing the most pronounced skewing to IgG2a, i.e. towards Th1 type of response. While the virosomal adjuvanted pandemic influenza vaccine efficiently induced CD4(+) T-cell response, with no further increase upon adjuvation, the CD8(+) T-cell responses induced with virosomal adjuvanted vaccine could be significantly improved upon additional adjuvation with MATRIX-M or MF59. All adjuvants demonstrated a dose sparing effect, i.e. in combination with the virosomal adjuvanted pandemic influenza vaccine they increased immune responses to comparable level independent of the tested vaccine dose. In conclusion, our results demonstrate that immune responses to a virosomal adjuvanted pandemic influenza vaccine can be further enhanced by add-on adjuvants, with MATRIX-M being overall the most potent adjuvant in combination with virosomes, followed by MF59 and finally aluminium-based adjuvants.     

Immune responses after fractional doses of inactivated poliovirus vaccine using newly developed intradermal jet injectors: A randomized controlled trial in Cuba

IntroductionThe World Health Organization recommends that, as part of the new polio endgame, a dose of inactivated poliovirus vaccine (IPV) be introduced by the end of 2015 in all countries using only oral poliovirus vaccine (OPV). Administration of fractional dose (1/5th of full dose) IPV (fIPV) intradermally may reduce costs, but its administration is cumbersome with BCG needle and syringe. We evaluated performance of two newly developed intradermal-only jet injectors and compared the immune response induced by fIPV with that induced by full-dose IPV.MethodsChildren between 12 and 20 months of age, who had previously received two doses of OPV, were enrolled in Camaguey, Cuba. Subjects received a single dose of IPV (either full-dose IPV intramuscularly with needle and syringe or fIPV intradermally administered with one of two new injectors or with BCG needle or a conventional needle-free injector). Serum was tested for presence of poliovirus neutralizing antibodies on day 0 (pre-IPV) and on days 3, 7 and 21 (post-vaccination).ResultsComplete data were available from 74.2% (728/981) subjects. Baseline median antibody titers were 713, 284, and 113 for poliovirus types 1, 2, and 3, respectively. Seroprevalence at study end were similar across the intervention groups (≥94.8%). The immune response induced with one new injector was similar to BCG needle and to the conventional injector; and superior to the other new injector. fIPV induced significantly lower boosting response compared to full-dose IPV. No safety concerns were identified.InterpretationOne of the two new injectors demonstrated its ability to streamline intradermal fIPV administration, however, further investigations are needed to assess the potential contribution of fIPV in the polio endgame plan.     

Alum boosts TH2-type antibody responses to whole-inactivated virus influenza vaccine in mice but does not confer superior protection

Clinical trials with pandemic influenza vaccine candidates have focused on aluminium hydroxide as an adjuvant to boost humoral immune responses. In this study we investigated the effect of aluminium hydroxide on the magnitude and type of immune response induced by whole-inactivated virus (WIV) vaccine. Balb/c mice were immunized once with a range of antigen doses (0.04-5 microg) of WIV produced from A/PR/8 virus, either alone or in combination with aluminium hydroxide. The hemagglutination inhibition (HI) titers of mice receiving WIV+aluminium hydroxide were 4-16-fold higher than HI titers in mice receiving the same dose of WIV alone, indicating the boosting effect of aluminium hydroxide. WIV induced a TH1 skewed humoral and cellular immune response, characterized by strong influenza-specific IgG2a responses and a high number of IFNgamma-secreting T cells. In contrast, immunization with WIV adsorbed to aluminium hydroxide resulted in skewing of this response to a TH2 phenotype (high IgG1 levels and a low number of IFNgamma-producing T cells). To assess the effect of the observed immune response skewing on viral clearance from the lungs mice immunized once with 1 microg WIV without or with aluminium hydroxide were challenged with A/PR/8 virus 4 weeks later. The immunized mice showed a significant decrease in viral lung titers compared to control mice receiving buffer. However, despite higher antibody titers, mice immunized with WIV adsorbed to aluminium hydroxide suffered from more severe weight loss and had significantly higher virus loads in their lung tissue than mice receiving WIV alone. Major difference between these groups of mice was the type of immune response induced, TH2 instead of TH1, indicating that a TH1 response plays a major role in viral clearance.     

Oral and fecal polio vaccine excretion following bOPV vaccination among Israeli infants

IntroductionInactivated polio virus (IPV) vaccinations are a mainstay of immunization schedules in developed countries, while oral polio vaccine (OPV) is administered in developing countries and is the main vaccine in outbreaks. Due to circulating wild poliovirus (WPV1) detection in Israel (2013), oral bivalent polio vaccination (bOPV) was administered to IPV primed children and incorporated into the vaccination regimen.ObjectivesWe aimed to determine the extent and timeframe of fecal and salivary polio vaccine virus (Sabin strains) shedding following bOPV vaccination among IPV primed children.MethodsFecal samples were collected from a convenience sample of infants and toddlers attending 11 Israeli daycare centers. Salivary samples were collected from infants and toddlers following bOPV vaccination.Results398 fecal samples were collected from 251 children (ages: 6–32 months), 168 received bOPV vaccination 4–55 days prior to sample collection. Fecal excretion continued among 80 %, 50 %, and 20 %, 2, 3, and 7 weeks following vaccination. There were no significant differences in the rate and duration of positive samples among children immunized with 3 or 4 IPV doses. Boys were 2.3-fold more likely to excrete the virus (p = 0.006). Salivary shedding of Sabin strains occurred in 1/47 (2 %) and 1/49 (2 %) samples 4, and 6 days following vaccination respectively.ConclusionsFecal detection of Sabin strains among IPV-primed children continues for 7 weeks; additional doses of IPV do not augment intestinal immunity; limited salivary shedding occurs for up to a week. This data can enhance understanding of intestinal immunity achieved by different vaccination schedules and guide recommendations for contact precautions of children following bOPV vaccination.     

Long-term evaluation of mucosal and systemic immunity and protection conferred by different polio booster vaccines

Oral polio vaccine (OPV) and Inactivated Polio Vaccine (IPV) have distinct advantages and limitations. IPV does not provide mucosal immunity and introduction of IPV to mitigate consequences of circulating vaccine-derived polio virus from OPV has very limited effect on transmission and OPV campaigns are essential for interrupting wild polio virus transmission, even in developed countries with a high coverage of IPV and protected sewer systems. The problem is magnified in many countries with limited resources. Requirement of refrigeration for storage and transportation for both IPV and OPV is also a major challenge in developing countries. Therefore, we present here long-term studies on comparison of a plant-based booster vaccine, which is free of virus and cold chain with IPV boosters and provide data on mucosal and systemic immunity and protection conferred by neutralizing antibodies.Mice were primed subcutaneously with IPV and boosted orally with lyophilized plant cells containing 1 μg or 25 μg polio viral protein 1 (VP1), once a month for three months or a single booster one year after the first prime. Our results show that VP1-IgG1 titers in single or double dose IPV dropped to background levels after one year of immunization. This decrease correlated with >50% reduction in seropositivity in double dose and <10% seropositivity in single dose IPV against serotype 1. Single dose IPV offered no or minimal protection against serotype 1 and 2 but conferred protection against serotype 3. VP1-IgA titers were negligible in IPV single or double dose vaccinated mice. VP1 antigen with two plant-derived adjuvants induced significantly high level and long lasting VP1-IgG1, IgA and neutralizing antibody titers (average 4.3–6.8 log2 titers). Plant boosters with VP1 and plant derived adjuvants maintained the same level titers from 29 to 400 days and conferred the same level of protection against all three serotypes throughout the duration of this study. Even during period, when no plant booster was given (∼260 days), VP1-IgG1 titers were maintained at high levels. Lyophilized plant cells expressing VP1 can be stored without losing efficacy, eliminating cold chain. Virus-free, cold-chain free vaccine is ready for further clinical development.     

Introduction of inactivated polio vaccine (IPV) into the routine immunization schedule of South Africa

South Africa is currently the only country on the African continent using inactivated polio vaccine (IPV) for routine immunization in a sequential schedule in combination with oral polio vaccine (OPV). IPV is a component of an injectable pentavalent vaccine introduced nationwide in April 2009 and administered according to EPI schedule at 6, 10 and 14 weeks with a booster dose at 18 months. OPV is administered at birth and together with the first IPV dose at 6 weeks, which stimulates gut immune system producing a memory IgA response (OPV), followed by IPV to minimize the risk of vaccine associated paralytic polio (VAPP). OPV is also given to all children under 5 years of age as part of regular mass immunizations campaigns. The decision to incorporate IPV into the routine schedule was not based on cost-effectiveness, which it is not. Other factors were taken into account: Firstly, the sequence benefits from the initial mucosal contact with live(vaccine) virus which promotes the IgA response from subsequent IPV, as well as herd immunity from OPV, together with the safety of IPV. Secondly, given the widespread and increasing use of IPV in the developed world, public acceptance of vaccination in general is enhanced in South Africa which is classified as an upper middle income developing country. Thirdly, to address equity concerns because of the growing use of IPV in the private sector. Fourthly, the advent of combination vaccines facilitated the incorporation of IPV into the EPI schedule.     

Lack of immune interference between inactivated polio vaccine and inactivated rotavirus vaccine co-administered by intramuscular injection in two animal species

A parenteral inactivated rotavirus vaccine (IRV) in development could address three problems with current live oral rotavirus vaccines (ORV): their lower efficacy in low and middle-income countries (LMICs), lingering concerns about their association with intussusception, and their requirement for a separate supply chain with large volume cold storage. Adding a new parenteral IRV to the current schedule of childhood immunizations would be more acceptable if it could be combined with another injectable vaccine such as inactivated polio vaccine (IPV). Current plans for polio eradication call for phasing out oral polio vaccine (OPV) and transitioning to IPV, initially in LMICs as a single dose booster after two doses of OPV and ultimately as a two dose schedule. Today in many LMICs, IPV is administered as a standalone vaccine, which involves a separate cold chain and is relatively costly. We therefore tested in two animal models formulations of IPV with IRV to determine whether co-administration might interfere with the immune response to each product and spare antigen dose for both vaccines. Our results demonstrate that IRV when adjuvanted with alum and administered alone or in combination with IPV did not impair the immune responses to either rotavirus or poliovirus serotypes 1, 2 and 3. Similarly, IPV when formulated and administered alone or together with IRV induced comparable levels of neutralizing antibody to poliovirus type 1, 2 and 3. Furthermore, comparable antibody titers were observed in animals vaccinated with low, middle or high dose of IPV or IRV in combination. This dose sparing and the lack of interference between IPV and IRV administered together represent another step to support the further development of this novel combination vaccine for children.     

Exploring the relationship between polio type 2 serum neutralizing antibodies and intestinal immunity using data from two randomized controlled trials of new bOPV-IPV immunization schedules

BackgroundInactivated polio vaccine (IPV) is now the only source of routine type 2 protection. The relationship, if any, between vaccine-induced type 2 humoral and intestinal immunity is poorly understood.MethodsTwo clinical trials in five Latin American countries of mixed or sequential bOPV-IPV schedules in 1640 infants provided data on serum neutralizing antibodies (NAb) and intestinal immunity, assessed as viral shedding following oral mOPV2 challenge. Analyses with generalized additive and quantile regression models examined the relationships between prechallenge NAb titers and proportion, duration and titers (magnitude) of viral shedding.ResultsWe found a statistically significant (p < .0001) but weak relationship between NAb titer at the time of mOPV2 challenge and the Shedding Index Endpoint, the mean log₁₀ stool viral titer over 4 post-challenge assessments. Day 28 post-challenge shedding was 13.4% (8.1%, 18.8%) lower and the Day 21 post-challenge median titer of shed virus was 3.10 log₁₀ (2.21, 3.98) lower for subjects with NAb titers at the ULOQ as compared with LLOQ on day of challenge. Overall, there was a weak but significant negative relationship, with high NAb titers associated with lower rates of viral shedding, an effect supported by subset analysis to elucidate between-country differences.ConclusionsTaken alone, the weak association between pre-challenge NAb titers following IPV or mixed/sequential bOPV/IPV immunization and differences in intestinal immunity is insufficient to predict polio type 2 intestinal immunity; even very high titers may not preclude viral shedding. Further research is needed to identify predictive markers of intestinal immunity in the context of global OPV cessation and IPV-only immunization.     

Intranasal and sublingual delivery of inactivated polio vaccine

Polio is on the brink of eradication. Improved inactivated polio vaccines (IPV) are needed towards complete eradication and for the use in the period thereafter. Vaccination via mucosal surfaces has important potential advantages over intramuscular injection using conventional needle and syringe, the currently used delivery method for IPV. One of them is the ability to induce both serum and mucosal immune responses: the latter may provide protection at the port of virus entry.The current study evaluated the possibilities of polio vaccination via mucosal surfaces using IPV based on attenuated Sabin strains. Mice received three immunizations with trivalent sIPV via intramuscular injection, or via the intranasal or sublingual route. The need of an adjuvant for the mucosal routes was investigated as well, by testing sIPV in combination with the mucosal adjuvant cholera toxin.Both intranasal and sublingual sIPV immunization induced systemic polio-specific serum IgG in mice that were functional as measured by poliovirus neutralization. Intranasal administration of sIPV plus adjuvant induced significant higher systemic poliovirus type 3 neutralizing antibody titers than sIPV delivered via the intramuscular route. Moreover, mucosal sIPV delivery elicited polio-specific IgA titers at different mucosal sites (IgA in saliva, fecal extracts and intestinal tissue) and IgA-producing B-cells in the spleen, where conventional intramuscular vaccination was unable to do so. However, it is likely that a mucosal adjuvant is required for sublingual vaccination. Further research on polio vaccination via sublingual mucosal route should include the search for safe and effective adjuvants, and the development of novel oral dosage forms that improve antigen uptake by oral mucosa, thereby increasing vaccine immunogenicity. This study indicates that both the intranasal and sublingual routes might be valuable approaches for use in routine vaccination or outbreak control in the period after complete OPV cessation and post-polio eradication.     

Effect of booster doses of poliovirus vaccine in previously vaccinated children,Clinical Trial Results 2013

BackgroundConsidering the current polio situation Pakistan needs vaccine combinations to reach maximum population level immunity. The trial assessed whether inactivated poliovirus vaccine (IPV) can be used to rapidly boost immunity among children in Pakistan.MethodsA five-arm randomized clinical trial was conducted among children (6–24 months, 5–6 years and 10–11 years). Children were randomized in four intervention arms as per the vaccines they received (bOPV, IPV, bOPV + vitamin A, and bOPV + IPV) and a control arm which did not receive any vaccine. Baseline seroprevalence of poliovirus antibodies and serological immune response 28 days after intervention were assessed.ResultsThe baseline seroprevalence was high for all serotypes and the three age groups [PV1: 97%, 100%, 96%, PV2: 86%, 100%, 99%, PV3: 83%, 95%, 87% for the three age groups respectively]. There was significantly higher rate of immune response observed in the study arms which included IPV (95–99%) compared with bOPV only arms (11–43%), [p < 0.001]; Vitamin A was not associated with improved immune response. Immune response rates in the IPV only arm and IPV + bOPV arm were similar [p > 0.5].ConclusionIPV has shown the ability to efficiently close existing immunity gaps in a vulnerable population of children in rural Pakistan.     

Humoral and cellular immunity induced by antigens adjuvanted with colloidal iron hydroxide

The immunopotentiating activities of colloidal iron hydroxide, a novel, experimental mineral adjuvant, and of aluminium hydroxide. the licensed adjuvant for human vaccines, were compared. Our studies revealed that colloidal iron hydroxide and aluminium hydroxide behaved comparably with respect to supporting induction of an antibody response to tetanus toxoid. Furthermore, mice immunized with both, the experimental vaccine (tick-borne encephalitis virus (TBEV) antigen adsorbed to colloidal iron hydroxide) or with a commercially available TBEV vaccine (adjuvanted with aluminium hydroxide), developed long-lasting antibody responses which protected the animals from TBEV infection even one year after vaccination. The use of colloidal iron hydroxide as adjuvant had the additional advantage to reproducibly support induction of HIV-1 envelope-specific cytotoxic T lymphocytes (CTL), when used as adjuvant for a HIV-1 env-carrying recombinant fowlpox virus and being applied via the subcutaneous route. Aluminium hydroxide was much less active in this respect. Non-adjuvanted recombinant fowlpox elicited CTLs only when given intravenously or intraperitoneally, vaccination routes considered not to be suitable for routine use in humans. Further studies to evaluate the use of colloidal iron as possible alternative and/or supplement for routinely used mineral adjuvants may therefore be warranted.     

Serological response and poliovirus excretion following different combined oral and inactivated poliovirus vaccines immunization schedules

A controlled study was conducted in Karachi, Pakistan to compare humoral and mucosal immune responses against polioviruses in infants who received oral poliovirus vaccine (OPV) at birth and at 6, 10, and 14 weeks according to the Expanded Program on Immunization (EPI) with infants who received either three doses of inactivated poliovirus vaccine (IPV) at 6, 10, and 14 weeks together with OPV or one additional dose of IPV at 14 weeks together, with the last dose of OPV. A total of 1429 infants were enrolled; 24-week serum specimens were available for 898 infants (63%). They all received a challenge dose of OPV type 3 at 24 weeks of age. The addition of three doses of IPV to three doses of OPV induced a significantly higher percentage of seropositive children at 24 weeks of age for polio 1 (97% versus 89%, P<0.001) and polio 3 (98% versus 92%) compared to the EPI schedule. However, the one supplemental dose of IPV at 14 weeks did not increase the serological response at 24 weeks. Intestinal immunity against the challenge dose was similar in the three groups. Combined schedules of OPV and IPV in the form of diphtheria-pertussis-tetanus-IPV vaccine (DPT-IPV) may be useful to accelerate eradication of polio in developing countries.     

Intradermal fractional-dose inactivated polio vaccine (fIPV) adjuvanted with double mutant Enterotoxigenic Escherichia coli heat labile toxin (dmLT) is well-tolerated and augments a systemic immune response to all three poliovirus serotypes in a randomized placebo-controlled trial

Eradication of poliomyelitis globally is constrained by fecal shedding of live polioviruses, both wild-type and vaccine-derived strains, into the environment. Although inactivated polio vaccines (IPV) effectively protect the recipient from clinical poliomyelitis, fecal shedding of live virus still occurs following infection with either wildtype or vaccine-derived strains of poliovirus. In the drive to eliminate the last cases of polio globally, improvements in both oral polio vaccines (OPV) (to prevent reversion to virulence) and injectable polio vaccines (to improve mucosal immunity and prevent viral shedding) are underway. The E. coli labile toxin with two or “double” attenuating mutations (dmLT) may boost immunologic responses to IPV, including at mucosal sites. We performed a double-blinded phase I controlled clinical trial to evaluate safety, tolerability, as well as systemic and mucosal immunogenicity of IPV adjuvanted with dmLT, given as a fractional (1/5th) dose intradermally (fIPV-dmLT). Twenty-nine volunteers with no past exposure to OPV were randomized to a single dose of fIPV-dmLT or fIPV alone. fIPV-dmLT was well tolerated, although three subjects had mild but persistent induration and hyperpigmentation at the injection site. A ≥ 4-fold rise in serotype-specific neutralizing antibody (SNA) titers to all three serotypes was seen in 84% of subjects receiving fIPV-dmLT vs. 50% of volunteers receiving IPV alone. SNA titers were higher in the dmLT-adjuvanted group, but only differences in serotype 1 were significant. Mucosal immune responses, as measured by polio serotype specific fecal IgA were minimal in both groups and differences were not seen. fIPV-dmLT may offer a benefit over IPV alone. Beyond NAB responses protecting the individual, studies demonstrating the ability of fIPV-dmLT to prevent viral shedding are necessary. Studies employing controlled human infection models, using monovalent OPV post-vaccine are ongoing. Studies specifically in children may also be necessary and additional biomarkers of mucosal immune responses in this population are needed.Clinicaltrials.gov Identifer: NCT03922061.     

The response to oral poliovaccine in persons aged 16-18 years.

Serum neutralizing antibodies to polioviruses were titrated in serum samples from 182 police cadets aged 16-18 years before and, in 168 of the cadets, 6 weeks after vaccination with a single dose of oral polio vaccine (OPV). Faecal excretion of poliovirus was also followed. Vaccination histories were obtained and confirmed whenever possible. Pre-vaccination antibody could not be detected against type 1 in 9-3% cadets, against type 2 in 2-7% and against type 3 in 7-7%. Absence of antibody to at least one virus type was found in 14-3% of the cadets. In 93 cadets in whom vaccination histories could be confirmed 40 had received only inactivated polio vaccine (IPV) previously; of these 23% lacked antibody to at least one virus type, and they had less intestinal immunity to a challenge dose of OPV than those previously given OPV. Only two of the cadets known to have had OPV were non-immune - both had received a single dose following full courses of IPV. However, cadets who had received OPV had their last dose of vaccine more recently (average 4-6 years) than those who had received only IPV (all 12 years or more). The serum antibody response to a single booster dose of OPV, and the faecal excretion of each type of virus after vaccination, showed an inverse relation to the corresponding pre-vaccination antibody concentration. A single dose of OPV did not reliably boost the immunity of those who possessed adequate immunity, and a failure to respond was also observed in a proportion of the cadets with no detectable antibody, mostly in the case of type 3 antibody and particularly if antibody to types 1 or 2 virus was also absent. No evidence was obtained that intestinal immunity could be expected in the absence of detectable circulating antibody. The reasons for the absence of a serological response to OPV in some subjects are discussed and consideration is given to the practical significance of the findings. It is suggested that reinforcement of polio immunity at school-leaving is important, particularly at the present time when many of those aged 16-18 years will have been vaccinated only with IPV. A single dose of OPV is not ideal for this purpose, not only because a small proportion of persons are liable to be left unprotected, but also because failure to produce a reliable boost in persons with adequate immunity at the time of vaccination gives rise to the possibility that they may become susceptible later in adult life.