Pertussis in Mexico from 2000 to 2019: A real-world study of incidence, vaccination coverage, and vaccine effectiveness.

BACKGROUND: The national immunization program in Mexico includes a 3-dose primary series of pertussis vaccine and a toddler booster dose. In Mexico, whole-cell pertussis vaccines (wP) were switched in 2007 to acellular pertussis vaccines (aP). METHODS: This retrospective study using Mexican National Databases of Health and population surveillance (2000-2019) assessed the incidence of pertussis, infant pertussis vaccination coverage, and vaccine effectiveness (VE) against clinically-diagnosed and/or laboratory-confirmed pertussis in children aged 6.5-18.5 or 24.5 months for the primary series, and children aged 18.5 or 24.5-48.5 months for the toddler booster. RESULTS: The incidence of pertussis sharply increased in 2012 and was highest in 2012, 2015, and 2016 (0.84-0.94/100,000 person-years). Coverage was highest for the first dose in the primary series, decreasing for each subsequent dose. The VE against notified pertussis was 96.4% (95% CI: 94.7, 97.6) for the first three doses of wP vaccine (2000-2007) and 95.7% (95% CI: 95.1, 96.2) for the first three doses of aP vaccine (2008-2019). CONCLUSIONS: Our findings suggested high levels of vaccine effectiveness overall were achieved for the aP and wP vaccines in Mexico between 2000 and 2019.

Immunogenicity and Safety of a Tetravalent Dengue Vaccine Administered Concomitantly or Sequentially With Quadrivalent Human Papillomavirus Vaccine in Boys and Girls 9-13 Years of Age in Malaysia: A Phase IIIb, Randomized, Open-label Study.

BACKGROUND: Incorporating dengue vaccination within existing vaccination programs could help improve dengue vaccine coverage. We assessed the immunogenicity and safety of a quadrivalent human papillomavirus (HPV) vaccine administered concomitantly or sequentially with a tetravalent dengue vaccine (CYD-TDV) in healthy children 9-13 years of age in Malaysia. METHODS: In this phase IIIb, open-label, multicenter study (NCT02993757), participants were randomized 1:1 to receive 3 CYD-TDV doses 6 months apart and 2 doses of quadrivalent HPV vaccine concomitantly with, or 1 month before (sequentially), the first 2 CYD-TDV doses. Only baseline dengue-seropositive participants received the 3 doses. Antibody levels were measured at baseline and 28 days after each injection using an enzyme-linked immunosorbent assay for HPV-6, -9, -16 and -18, and the 50% plaque reduction neutralization test for the 4 dengue serotypes; immunogenicity results are presented for baseline dengue-seropositive participants. Safety was assessed throughout the study for all participants. RESULTS: At baseline, 197 of 528 (37.3%) randomized participants were dengue-seropositive [n = 109 (concomitant group) and n = 88 (sequential group)]. After the last HPV vaccine dose, antibody titers for HPV among baseline dengue-seropositive participants were similar between treatment groups, with between-group titer ratios close to 1 for HPV-6 and 0.8 for HPV-11, -16, and -18. After CYD-TDV dose 3, dengue antibody titers were similar between treatment groups for all serotypes [between-group ratios ranged from 0.783 (serotype 2) to 1.07 (serotype 4)]. No safety concerns were identified. CONCLUSIONS: The immunogenicity and safety profiles of CYD-TDV and quadrivalent HPV vaccines were unaffected when administered concomitantly or sequentially in dengue-seropositive children.

Immunogenicity and Safety of a Tetravalent Dengue Vaccine Administered Concomitantly or Sequentially With Tdap Vaccine: Randomized Phase IIIb Trial in Healthy Participants 9-60 Years of Age in the Philippines.

BACKGROUND: Incorporating dengue vaccination into existing childhood vaccination programs could increase vaccine coverage. This study assessed the safety and immunogenicity of concomitant versus sequential administration of the combined tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine and the tetravalent dengue vaccine (CYD-TDV). METHODS: This phase IIIb, randomized, open-label, multicenter study was conducted in the Philippines in individuals 9-≤60 years of age (NCT02992418). Participants were to receive 3 CYD-TDV doses 6 months apart, the first dose administered either concomitantly or sequentially (28 days post-Tdap). Antibody levels were measured at baseline and 28 days post-first doses of Tdap vaccine and CYD-TDV, using enzyme-linked immunosorbent assay (pertussis, tetanus), micrometabolic inhibition test-toxin neutralization assay (diphtheria) and plaque reduction neutralization test (dengue). Immunogenicity was assessed for all participants, and statistical analysis reported for baseline dengue seropositive participants. Safety was assessed throughout. RESULTS: Among 688 randomized participants, 629 (91.4%) were baseline dengue seropositive (concomitant group, n = 314 and sequential group, n = 315). After the first dose, non-inferiority of immune responses between concomitant and sequential vaccination was achieved; between-group geometric mean antibody concentration ratios were close to 1 for anti-PT, anti-FHA, anti-PRN and anti-FIM, between-group differences in percent achieving seroprotection (titers ≥0.1 IU/mL) were 0.26% (diphtheria) and 0.66% (tetanus), and between-group geometric mean antibody titer ratios were close to 1 for dengue serotypes 1-4. Safety profiles in both study groups were comparable. CONCLUSIONS: CYD-TDV and Tdap vaccine administered concomitantly or sequentially in baseline dengue seropositive participants elicited comparable immunogenicity and safety profiles.

Mortality among Hospitalized Dengue Patients with Comorbidities in Mexico, Brazil, and Colombia.

Dengue patients with comorbidities may be at higher risk of death. In this cross-sectional study, healthcare databases from Mexico (2008-2014), Brazil (2008-2015), and Colombia (2009-2017) were used to identify hospitalized dengue cases and their comorbidities. Case fatality rates (CFRs), relative risk, and odds ratios (OR) for in-hospital mortality were determined. Overall, 678,836 hospitalized dengue cases were identified: 68,194 from Mexico, 532,821 from Brazil, and 77,821 from Colombia. Of these, 35%, 5%, and 18% were severe dengue, respectively. Severe dengue and age ≥ 46 years were associated with increased risk of in-hospital mortality. Comorbidities were identified in 8%, 1%, and 4% of cases in Mexico, Brazil, and Colombia, respectively. Comorbidities increased hospitalized dengue CFRs 3- to 17-fold; CFRs were higher with comorbidities regardless of dengue severity or age. The odds of in-hospital mortality were significantly higher in those with pulmonary disorders (11.6 [95% CI 7.4-18.2], 12.7 [95% CI 9.3-17.5], and 8.0 [95% CI 4.9-13.1] in Mexico, Brazil, and Colombia, respectively), ischemic heart disease (23.0 [95% CI 6.6-79.6], 5.9 [95% CI 1.4-24.6], and 7.0 [95% CI 1.9-25.5]), and renal disease/failure (8.3 [95% CI 4.8-14.2], 8.0 [95% CI 4.5-14.4], and 9.3 [95% CI 3.1-28.0]) across the three countries; the odds of in-hospital mortality from dengue with comorbidities was at least equivalent or higher than severe dengue alone (4.5 [95% CI 3.4-6.1], 9.6 [95% CI 8.6-10.6], and 9.0 [95% CI 6.8-12.0). In conclusion, the risk of death because of dengue increases with comorbidities independently of age and/or disease severity.

Immunogenicity and safety of a tetravalent dengue vaccine and a bivalent HPV vaccine given concomitantly or sequentially in girls aged 9 to 14 years in Mexico.

Dengue is endemic in several regions, and the global incidence is increasing. The recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV) is recommended for dengue seropositive individuals ≥ 9 years. Human papillomavirus (HPV) vaccination is recommended for girls aged 9-14 years to prevent HPV infection-related cancers. This study assessed the immunogenicity and safety of a bivalent HPV (types 16 and 18) vaccine and CYD-TDV when co-administered concomitantly or sequentially. This was a Phase IIIb, randomized, open-label, multicenter study in girls aged 9-14 years in Mexico (NCT02979535). Participants were randomized 1:1 to receive three doses of CYD-TDV 6 months apart and two doses of bivalent HPV vaccine either concomitantly with, or 1 month before (sequentially), the first 2 CYD-TDV doses. Antibody levels were measured at baseline and 28-days after each vaccine dose for all participants, using an enzyme-linked immunosorbent assay for HPV-16 and HPV-18 antibodies, and a plaque reduction neutralization test for the four dengue serotypes; results are reported only for participants who were seropositive at baseline. Safety was assessed for all randomized participants throughout the study. Of the randomized participants, 305/478 (63.8%) were seropositive for dengue at baseline: 154 in the concomitant group and 151 in the sequential group. After the last HPV vaccine dose, the antibody titers for HPV were comparable in seropositive participants between treatment groups, with between group titer ratios of 0.966 for HPV-16 and 0.999 for HPV-18. After dose 3 of CYD-TDV, antibody titers were comparable for the concomitant and sequential groups across all serotypes, with between-group ratios close to 1 (serotype 1: 0.977; serotype 2: 0.911; serotype 3: 0.921; serotype 4: 0.931). CYD-TDV and a bivalent HPV vaccine administered concomitantly or sequentially in dengue seropositive girls aged 9-14 years elicited comparable immune responses with similar safety profiles.

Comorbidities increase in-hospital mortality in dengue patients in Brazil.

Dengue remains an unmet public health burden. We determined risk factors for dengue in-hospital mortality in Brazil. Of 326,380 hospitalised dengue cases in 9-45-year-old individuals, there were 971 deaths. Risk of dying was 11-times higher in the presence of underlying common comorbidities (renal, infectious, pulmonary disease and diabetes), similar to the risk of dying from severe dengue and much higher with the combination. Ensuring access to integrated dengue preventative measures in individuals aged ≥ 9 years including those with comorbidities may help achieve the WHO objective of 50% reduction in mortality and 25% reduction in morbidity due to dengue by 2020.

Effect of Dengue Serostatus on Dengue Vaccine Safety and Efficacy.

BACKGROUND: In efficacy trials of a tetravalent dengue vaccine (CYD-TDV), excess hospitalizations for dengue were observed among vaccine recipients 2 to 5 years of age. Precise risk estimates according to observed dengue serostatus could not be ascertained because of the limited numbers of samples collected at baseline. We developed a dengue anti-nonstructural protein 1 (NS1) IgG enzyme-linked immunosorbent assay and used samples from month 13 to infer serostatus for a post hoc analysis of safety and efficacy. METHODS: In a case-cohort study, we reanalyzed data from three efficacy trials. For the principal analyses, we used baseline serostatus determined on the basis of measured (when baseline values were available) or imputed (when baseline values were missing) titers from a 50% plaque-reduction neutralization test (PRNT50), with imputation conducted with the use of covariates that included the month 13 anti-NS1 assay results. The risk of hospitalization for virologically confirmed dengue (VCD), of severe VCD, and of symptomatic VCD according to dengue serostatus was estimated by weighted Cox regression and targeted minimum loss-based estimation. RESULTS: Among dengue-seronegative participants 2 to 16 years of age, the cumulative 5-year incidence of hospitalization for VCD was 3.06% among vaccine recipients and 1.87% among controls, with a hazard ratio (vaccine vs. control) through data cutoff of 1.75 (95% confidence interval [CI], 1.14 to 2.70). Among dengue-seronegative participants 9 to 16 years of age, the cumulative incidence of hospitalization for VCD was 1.57% among vaccine recipients and 1.09% among controls, with a hazard ratio of 1.41 (95% CI, 0.74 to 2.68). Similar trends toward a higher risk among seronegative vaccine recipients than among seronegative controls were also found for severe VCD. Among dengue-seropositive participants 2 to 16 years of age and those 9 to 16 years of age, the cumulative incidence of hospitalization for VCD was 0.75% and 0.38%, respectively, among vaccine recipients and 2.47% and 1.88% among controls, with hazard ratios of 0.32 (95% CI, 0.23 to 0.45) and 0.21 (95% CI, 0.14 to 0.31). The risk of severe VCD was also lower among seropositive vaccine recipients than among seropositive controls. CONCLUSIONS: CYD-TDV protected against severe VCD and hospitalization for VCD for 5 years in persons who had exposure to dengue before vaccination, and there was evidence of a higher risk of these outcomes in vaccinated persons who had not been exposed to dengue. (Funded by Sanofi Pasteur; ClinicalTrials.gov numbers, NCT00842530 , NCT01983553 , NCT01373281 , and NCT01374516 .).

Comorbidities increase in-hospital mortality in dengue patients in Brazil

Dengue remains an unmet public health burden. We determined risk factors for dengue in-hospital mortality in Brazil. Of 326,380 hospitalised dengue cases in 9-45-year-old individuals, there were 971 deaths. Risk of dying was 11-times higher in the presence of underlying common comorbidities (renal, infectious, pulmonary disease and diabetes), similar to the risk of dying from severe dengue and much higher with the combination. Ensuring access to integrated dengue preventative measures in individuals aged ≥ 9 years including those with comorbidities may help achieve the WHO objective of 50% reduction in mortality and 25% reduction in morbidity due to dengue by 2020.

Immunogenicity of a 23-valent pneumococcal polysaccharide vaccine among Mexican children.

BACKGROUND AND AIMS: Streptococcus pneumoniae infection continues to be a major source of morbidity and mortality in children in Mexico. The aim of this study was to evaluate the immune response to six serotypes in children <5 years of age after immunization with a 23-valent pneumococcal polysaccharide vaccine. METHODS: A prospective study was conducted among children aged from 18 months to 4 years. Pre- and postvaccination titers for the serotypes selected in this project demonstrate a substantial response among all age groups. RESULTS: We identified mild adverse events in 62% of the participants in this study. No serious adverse events were reported during the study. CONCLUSIONS: Pneumococcal polysaccharide vaccine produced adequate immunogenicity in all age groups evaluated.

Serological protection induced by Haemophilus influenzae Type B conjugate vaccine in Mexican children: is a booster dose of the vaccine needed?

We determined the seroprevalence of protective antibodies against Hib in Mexican children under the age of five using a standardized enzyme-linked immunosorbent assay. Hib antibodies (≥ 0.15 µg/ml) were present in 95.34% (±1.14% [seroprevalence ± standard error]) of samples. Fewer children aged 30 to 47 months had protective Hib antibody levels (91.45% ± 2.60%) than children from 12 to 29 and 48 to 59 months (97.3% ± 1.34% and 97.44% ± 1.80%, respectively).

The safety and immunogenicity of influenza vaccine in children with asthma in Mexico.

BACKGROUND: The morbidity and mortality associated with influenza is substantial in children with asthma. There are no available data on the safety and immunogenicity of influenza vaccine in children with asthma in Latin America. Furthermore, it is unclear if influenza vaccination may cause asthma exacerbations. METHODS: We conducted a placebo-controlled trial to investigate the safety and immunogenicity of an inactivated trivalent split virus influenza vaccine in children with asthma in Mexico. We also measured the impact of influenza vaccination on pulmonary function tests in this population. RESULTS: The inactivated influenza vaccine was immunogenic and safe in terms of local and systemic side effects compared to placebo. We observed no significant impact on pulmonary function tests among vaccine recipients. CONCLUSIONS: Given the significant morbidity associated with influenza in children, strategies to promote increased influenza vaccination coverage in this high-risk group in Latin America and elsewhere are urgently needed.

[Immunogenicity and safety of the influenza vaccine, in a population older than 55-years in Mexico]. / Inmunogenicidad y tolerancia de una vacuna contra influenza, en una población mexicana mayor de 55 años de edad.

OBJECTIVE: To confirm the immunogenicity and tolerance of the inactivated, fractionated, and purified influenza vaccine, in a Mexican adult population aged 55 and older, medically served at a Petróleos Mexicanos Hospital (Pemex, Mexican Oil Company). MATERIAL AND METHODS: The study was conducted between November and December, 2000, among ninety adult subjects aged 55 years and older who were seen at the Hospital Central Sur Pemex. The primary endpoints regarding immunogenicity were the percentage of individuals with protective antibodies targeting hemagglutinins higher than or equal to 1:40, and the percentage of subjects who seroconverted as measured by a four-fold increase in protective antibody production. Secondary endpoints included the frequency of local and systemic reactions to the vaccine. An additional criterion that was evaluated included antigen-antibody affinity assays to measure the polyclonal antibody response to the vaccine and the specific generation of high-affinity antibodies to viral proteins, before and after vaccination. RESULTS: The antibody protection rate was 95.6% against the HINI strain, 98.9% against the H3N2 strain, and a 100% against the B/Yamanashi strain. Seroconversion to the HINI strain was elicited in 74.4% of subjects, to the H3N2 strain in 88.9%, and to the B/Yamanashi strain in 82.2%. Eighteen (20%) subjects developed local reactions; 17 (18.8%) developed a systemic reaction post vaccination at day 5 and nine subjects (10%) at day 28. Local reactions consisted of pain in 10 (11.1%) subjects, redness in 8 (8.8%), and induration in 6 (6.6%). General malaise, headache, and fever were identified in 10, 8.8, and 0% of subjects, respectively, at day 5, and in 4.4, 6.6, and 0%, respectively, at day 28. CONCLUSIONS: Influenza vaccine was highly immunogenic in a healthy Mexican adult population aged 55 years and older. The generation of high-affinity antibodies to the virus after vaccination was also demonstrated. Local and systemic adverse reactions to the vaccine identified in our study were similar to those in previous reports. The results of this study can be extrapolated to other health institutions serving this adult population to increase influenza vaccine coverage rates.

Inmunogenicidad y tolerancia de una vacuna contra influenza, en una población mexicana mayor de 55 años de edad / Immunogenicity and safety of the influenza vaccine, in a population older than 55-years in Mexico

OBJETIVO: Verificar la inmunogenicidad y tolerancia de una vacuna purificada, inactivada y fraccionada contra influenza, en adultos mexicanos derechohabientes de Petróleos Mexicanos (Pemex). MATERIAL Y MÉTODOS: Se incluyeron 90 adultos mayores de 55 años de edad, derechohabientes de los servicios médicos del Hospital Central Sur Pemex, durante los meses de noviembre y diciembre de 2000. Los criterios evaluados en relación con la inmunogenicidad incluyeron el porcentaje de sujetos protegidos, cuantificados por medio de anticuerpos antihemaglutininas superior o igual a 1:40, así como por el porcentaje de seroconversión determinado por el título inicial de anticuerpos multiplicado por un factor 4X. Los criterios secundarios fueron la frecuencia de reacciones adversas tanto locales como sistémicas. Se realizaron estudios de afinidad antígeno-anticuerpo para determinar la respuesta policlonal de anticuerpos y de anticuerpos de alta afinidad prevacunación y posvacunación. Se calcularon frecuencias y porcentajes. RESULTADOS: Se identificó una seroprotección en 95.6 por ciento de los sujetos a la cepa H1N1, de 98.9 por ciento a la cepa H3N2 y de 100 por ciento a la cepa B/ Yamanashi. En cuanto a los porcentajes de seroconversión, se identificó un incremento 4X de 74.4 para la cepa H1N1, de 88.9 para la cepa H3N2, y de 82.2 para la cepa B / Yamanashi. Un total de 18 individuos (20 por ciento) presentaron reacciones locales, mientras que 17 (18.8 por ciento) presentaron reacciones sistémicas a los cinco días posvacunación y nueve sujetos (10 por ciento) a los 28 días. Las reacciones locales a los cinco días consistieron en dolor, en 10 individuos (11.1 por ciento); enrojecimiento, en ocho (8.8 por ciento), e induración, en seis (6.6 por ciento). Malestar general, cefalea y fiebre se presentaron a los cinco días en 10, 8.8, y 0 por ciento de individuos, respectivamente, y en 4.4, 6.6, y 0 por ciento, respectivamente, a los 28 días. CONCLUSIONES: Esta vacuna contra influenza demostró ser altamente inmunogénica en adultos mexicanos mayores de 55 años de edad. Se demostró también la producción de anticuerpos de alta afinidad contra el virus, posterior a la vacunación. Además, se identificó una frecuencia de reacciones locales y sistémicas similares a las previamente reportadas...