Pertussis vaccines containing three or five pertussis antigens are recommended in pregnancy in many countries, but no studies have compared the effect on infants' antigen-specific immunoglobulin G ...(IgG) concentrations. The aim of this study was to compare anti-pertussis IgG responses following primary immunization in infants of mothers vaccinated with TdaP
-IPV (low dose diphtheria toxoid, tetanus toxoid, acellular pertussis five antigens and inactivated polio) or TdaP
-IPV in pregnancy (three pertussis antigens).
This multi-centre phase IV randomized clinical trial was conducted in a tertiary referral centre and primary care sites in England. Women were randomized to receive TdaP
-IPV (n = 77) or TdaP
-IPV (n = 77) at 28-32 gestational weeks. A non-randomized control group of 44 women who had not received a pertussis-containing vaccine in pregnancy and their 47 infants were enrolled post-partum.
Following infant primary immunization, there was no difference in the geometric mean concentrations (GMCs) of anti-pertussis toxin, filamentous haemagglutinin or pertactin IgG between infants born to women vaccinated with TdaP
-IPV (n = 67) or TdaP
-IPV (n = 63). However, the GMC of anti-pertussis toxin IgG was lower in infants born to TdaP
-IPV- and TdaP
-IPV-vaccinated mothers compared to infants born to unvaccinated mothers (n = 45) (geometric mean ratio 0.71 0.56-0.90 and 0.78 0.61-0.98, respectively); by 13 months of age, this difference was no longer observed.
Blunting of anti-pertussis toxin IgG response following primary immunization occurs in infants born to women vaccinated with TdaP
-IPV and TdaP
-IPV, with no difference between maternal vaccines. The blunting effect had resolved by 13 months of age. These results may be helpful for countries considering which pertussis-containing vaccine to recommend for use in pregnancy.
ClinicalTrials.gov , NCT02145624 , registered 23 May 2014.
Given the importance of flexible use of different COVID-19 vaccines within the same schedule to facilitate rapid deployment, we studied mixed priming schedules incorporating an adenoviral-vectored ...vaccine (ChAdOx1 nCoV-19 ChAd, AstraZeneca), two mRNA vaccines (BNT162b2 BNT, Pfizer–BioNTech, and mRNA-1273 m1273, Moderna) and a nanoparticle vaccine containing SARS-CoV-2 spike glycoprotein and Matrix-M adjuvant (NVX-CoV2373 NVX, Novavax).
Com-COV2 is a single-blind, randomised, non-inferiority trial in which adults aged 50 years and older, previously immunised with a single dose of ChAd or BNT in the community, were randomly assigned (in random blocks of three and six) within these cohorts in a 1:1:1 ratio to receive a second dose intramuscularly (8–12 weeks after the first dose) with the homologous vaccine, m1273, or NVX. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentrations measured by ELISA in heterologous versus homologous schedules at 28 days after the second dose, with a non-inferiority criterion of the GMR above 0·63 for the one-sided 98·75% CI. The primary analysis was on the per-protocol population, who were seronegative at baseline. Safety analyses were done for all participants who received a dose of study vaccine. The trial is registered with ISRCTN, number 27841311.
Between April 19 and May 14, 2021, 1072 participants were enrolled at a median of 9·4 weeks after receipt of a single dose of ChAd (n=540, 47% female) or BNT (n=532, 40% female). In ChAd-primed participants, geometric mean concentration (GMC) 28 days after a boost of SARS-CoV-2 anti-spike IgG in recipients of ChAd/m1273 (20 114 ELISA laboratory units ELU/mL 95% CI 18 160 to 22 279) and ChAd/NVX (5597 ELU/mL 4756 to 6586) was non-inferior to that of ChAd/ChAd recipients (1971 ELU/mL 1718 to 2262) with a GMR of 10·2 (one-sided 98·75% CI 8·4 to ∞) for ChAd/m1273 and 2·8 (2·2 to ∞) for ChAd/NVX, compared with ChAd/ChAd. In BNT-primed participants, non-inferiority was shown for BNT/m1273 (GMC 22 978 ELU/mL 95% CI 20 597 to 25 636) but not for BNT/NVX (8874 ELU/mL 7391 to 10 654), compared with BNT/BNT (16 929 ELU/mL 15 025 to 19 075) with a GMR of 1·3 (one-sided 98·75% CI 1·1 to ∞) for BNT/m1273 and 0·5 (0·4 to ∞) for BNT/NVX, compared with BNT/BNT; however, NVX still induced an 18-fold rise in GMC 28 days after vaccination. There were 15 serious adverse events, none considered related to immunisation.
Heterologous second dosing with m1273, but not NVX, increased transient systemic reactogenicity compared with homologous schedules. Multiple vaccines are appropriate to complete primary immunisation following priming with BNT or ChAd, facilitating rapid vaccine deployment globally and supporting recognition of such schedules for vaccine certification.
UK Vaccine Task Force, Coalition for Epidemic Preparedness Innovations (CEPI), and National Institute for Health Research. NVX vaccine was supplied for use in the trial by Novavax.
Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation. However, we have previously reported that heterologous schedules incorporating an adenoviral ...vectored vaccine (ChAdOx1 nCoV-19, AstraZeneca; hereafter referred to as ChAd) and an mRNA vaccine (BNT162b2, Pfizer–BioNTech; hereafter referred to as BNT) at a 4-week interval are more reactogenic than homologous schedules. Here, we report the safety and immunogenicity of heterologous schedules with the ChAd and BNT vaccines.
Com-COV is a participant-blinded, randomised, non-inferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged 50 years and older with no or well controlled comorbidities and no previous SARS-CoV-2 infection by laboratory confirmation were eligible and were recruited at eight sites across the UK. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n=100) were enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELISA) at 28 days after boost, when comparing ChAd/BNT with ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered non-inferior to the approved homologous schedules if the lower limit of the one-sided 97·5% CI of the GMR of these comparisons was greater than 0·63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139.
Between Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57·8 years (SD 4·7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12 906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9·2 (one-sided 97·5% CI 7·5 to ∞). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14 080 ELU/mL), with a GMR of 0·51 (one-sided 97·5% CI 0·43 to ∞). Four serious adverse events occurred across all groups, none of which were considered to be related to immunisation.
Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines.
UK Vaccine Task Force and National Institute for Health Research.
Introduction. In England, antenatal pertussis immunization using a tetanus/low-dose diphtheria/5-component acellular-pertussis/inactivated-polio (TdaP5/IPV) vaccine was introduced in October 2012. We ...assessed infant responses to antigens in the maternal vaccine and to those conjugated to tetanus (TT) or the diphtheria toxin variant, CRM. Methods. Infants of 141 TdaP5/IPV-vaccinated mothers in Southern England immunized with DTaP5/IPV/Haemophilus influenzae b (Hib-TT) vaccine at 2-3-4 months, 13-valent pneumococcal vaccine (PCV13, CRM-conjugated) at 2–4 months and 1 or 2 meningococcal C vaccine (MCC-CRM- or MCC-TT) doses at 3–4 months had blood samples taken at 2 and/or 5 months of age. Results. Antibody responses to pertussis toxin (PT), filamentous hemagglutinin (FHA), fimbriae 2 + 3 (FIMs), diphtheria, tetanus, Hib, MCC and PCV13 serotypes were compared to responses in a historical cohort of 246 infants born to mothers not vaccinated in pregnancy. Infants had high pertussis antibody concentrations pre-immunization but only PT antibodies increased post-immunization (fold-change, 2.64; 95% confidence interval CI, 2.12–3.30; P < .001), whereas FHA antibodies fell (fold-change, 0.56; 95% CI, .48–.65; P < .001). Compared with infants of unvaccinated mothers, PT, FHA, and FIMs antibodies were lower post-vaccination, with fold-differences of 0.67 (0.58–0.77; P < .001), 0.62 (0.54–0.71; P < .001) and 0.51 (0.42–0.62; P < .001), respectively. Antibodies to diphtheria and some CRM-conjugated antigens were also lower, although most infants achieved protective thresholds; antibodies to tetanus and Hib were higher. Conclusions. Antenatal pertussis immunization results in high infant pre-immunization antibody concentrations, but blunts subsequent responses to pertussis vaccine and some CRM-conjugated antigens. In countries with no pertussis booster until school age, continued monitoring of protection against pertussis is essential.
The use of the multicomponent meningococcal vaccine 4CMenB in the UK schedule at 2, 4, and 12 months of age has been shown to be 59·1% effective at preventing invasive group B meningococcal disease. ...Here, we report the first data on the immunogenicity of this reduced-dose schedule to help to interpret this effectiveness estimate.
In this multicentre, parallel-group, open-label, randomised clinical trial, infants aged up to 13 weeks due to receive their primary immunisations were recruited via child health database mailouts in Oxfordshire and via general practice surgeries in Gloucestershire and Hertfordshire. Infants were randomly assigned (1:1) with permuted block randomisation to receive a 2 + 1 (2, 4, and 12 months; group 1) or 1 + 1 (3 and 12 months; group 2) schedule of the 13-valent pneumococcal conjugate vaccine (PCV13). All infants also received 4CMenB at 2, 4, and 12 months of age, and had blood samples taken at 5 and 13 months. Participants and clinical trial staff were not masked to treatment allocation. Proportions of participants with human complement serum bactericidal antibody (hSBA) titres of at least 4 were determined for group B meningococcus (MenB) reference strains 5/99 (Neisserial Adhesin A NadA), NZ98/254 (porin A), and 44/76-SL (factor H binding protein fHbp). Geometric mean titres (GMTs) with 95% CIs were also calculated, and concomitant vaccine responses (group C meningococcus MenC, Haemophilus influenzae b Hib, tetanus, diphtheria, and pertussis) were compared between groups. The primary outcome was PCV13 immunogenicity, with 4CMenB immunogenicity and reactogenicity as secondary outcomes. All individuals by randomised group with a laboratory result were included in the analysis. The study is registered on the EudraCT clinical trials database, 2015-000817-32, and ClinicalTrials.gov, NCT02482636, and is complete.
Between Sept 22, 2015, and Nov 1, 2017, of 376 infants screened, 213 were enrolled (106 in group 1 and 107 in group 2). 204 samples post-primary immunisation and 180 post-boost were available for analysis. The proportion of participants with hSBA of at least 4 was similar in the two study groups. For strain 5/99, all participants developed hSBA titres above 4 in both groups and at both timepoints. For strain 44/76-SL, these proportions were 95·3% (95% CI 88·5–98·7) or above post-priming (82 of 86 participants in group 1), and 92·4% (84·2–97·2) or above post-boost (73 of 79 participants in group 1). For strain NZ98/254, these proportions were 86·5% (78·0–92·6) or above post-priming (83 of 96 participants in group 2) and 88·6% (79·5–94·7) or above post-boost (70 of 79 participants in group 1). The MenC rabbit complement serum bactericidal antibody (rSBA) titre in group 1 was significantly higher than in group 2 (888·3 vs 540·4; p=0·025). There was no significant difference in geometric mean concentrations between groups 1 and 2 for diphtheria, tetanus, Hib, and pertussis post-boost. A very small number of children did not have a protective response against 44/76-SL and NZ98/254. Local and systemic reactions were similar between the two groups, apart from the 3 month timepoint when one group received an extra dose of PCV13 and recorded more systemic reactions.
These data support the recent change to the licensed European schedule for 4CMenB to add an infant 2 + 1 schedule, as used in the routine UK vaccine programme with an effectiveness of 59·1%. When compared with historical data, our data do not suggest that effectiveness would be higher with a 3 + 1 schedule, however a suboptimal boost response for bactericidal antibodies against vaccine antigen fHbp suggests a need for ongoing surveillance for vaccine breakthroughs due to fHbp-matched strains. Changing from a 2 + 1 to a 1 + 1 schedule for PCV13 for the UK is unlikely to affect protection against diphtheria, tetanus, and Hib, however an unexpected reduction in bactericidal antibodies against MenC seen with the new schedule suggests that ongoing surveillance for re-emergent MenC disease is important.
Bill & Melinda Gates Foundation and the National Institute for Health Research.
Maternal antenatal pertussis-containing vaccination is recommended for the prevention of neonatal pertussis, but the ability of maternal vaccination to protect premature infants is unknown. We ...hypothesized that that infants born prematurely to antenatally vaccinated women would have higher pertussis antibody concentrations than those born to unvaccinated women.
Mothers had been offered a combined tetanus, diphtheria, 5-component acellular pertussis, inactivated polio vaccine from 28 weeks' gestation as part of their routine antenatal care. Premature infants of vaccinated and unvaccinated mothers enrolled in a randomized controlled trial of pneumococcal conjugate vaccine schedules had antibody concentrations (pertussis toxin, filamentous hemoagglutinin FHA, and fimbriae 2 and 3) measured at 2 months (before primary vaccination), 5 months (1 month after primary vaccination), and 12 months of age.
Mothers of 31 (19%) of 160 premature infants had received combined tetanus, diphtheria, 5-component acellular pertussis, inactivated polio vaccine in pregnancy. Compared with infants of unvaccinated mothers, those born to vaccinated mothers had significantly higher antibody concentrations at 2 months for all measured vaccine antigens (P < .001). The number of days between maternal vaccination and delivery and immunoglobulin G concentration at 2 months of age was positively correlated for pertussis toxin (P = .011) and FHA (P = .001). After primary immunization, infants of vaccinated mothers had significantly lower antibody concentrations for FHA (P = .003) compared with infants of unvaccinated mothers; these differences had resolved by 12 months of age.
Maternal vaccination administered early in the third trimester may provide protection for infants born prematurely.
Premature infants have a higher risk of invasive pneumococcal disease and are more likely to have lower vaccine responses compared with term infants. Increasingly, immunization schedules are ...including a reduced, 2-dose, pneumococcal conjugate vaccine priming schedule. Our goal was to assess the immunogenicity of 3 commonly used 13-valent pneumococcal conjugate vaccine (PCV13) priming schedules in premature infants and their response to a 12-month booster dose.
Premature infants (<35 weeks' gestation) were randomized to receive PCV13 at 2 and 4 months (reduced schedule); 2, 3, and 4 months (accelerated schedule); or 2, 4, and 6 months (extended schedule). All infants received a 12-month PCV13 booster. Serotype-specific pneumococcal immunoglobulin G (IgG) for PCV13 serotypes was measured by using enzyme-linked immunosorbent assay 1 month after the primary and booster vaccinations.
A total of 210 infants (median birth gestation, 29(+6) weeks; range, 23(+2)-34(+6) weeks) were included. After the primary vaccination, 75% (95% confidence interval CI, 62-85), 88% (95% CI, 76-95), and 97% (95% CI, 87-99) of participants had protective antibody concentrations for at least one-half the PCV13 serotypes for the reduced, accelerated, and extended schedules, respectively. After the booster vaccination, participants receiving the extended schedule had significantly lower (P < .05) geometric mean concentrations compared with reduced (for 9 of 13 serotypes) and accelerated (for 4 of 13 serotypes) schedules, but nearly all participations, regardless of schedule or serotype, had seroprotective IgG concentrations.
A reduced priming schedule of PCV13 resulted in higher post-booster IgG concentrations but lower post-primary concentrations. The optimum vaccine schedule for preterm infants will therefore depend on when they are most at risk for invasive pneumococcal disease.
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