Efficacy and immunogenicity of influenza vaccine in HIV-infected children: a randomized, double-blind, placebo controlled trial
Madhi, Shabir A.a,b,c; Dittmer, Sylviad; Kuwanda, Locadiahb,c; Venter, Marietjiea; Cassim, Haseenad; Lazarus, Ericad; Thomas, Teenad; Liberty, Afaafd; Treurnich, Florettea; Cutland, Clare L.b,c; Weinberg, Adrianae; Violari, Avyd
aNational Institute of Communicable Diseases, Centre for Respiratory and Meningitis Diseases, Sandringham
bDepartment of Science and Technology/National Research Foundation, Vaccine Preventable Diseases
cMedical Research Council: Respiratory & Meningeal Pathogens Research Unit
dPerinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa
eDepartment of Pediatrics, Medicine and Pathology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA.
Correspondence to Shabir A. Madhi, National Institute for Communicable Diseases, National Health Laboratory Service, 1 Modderfontein Road, Sandringham, 2131 Johannesburg, Gauteng, South Africa. Tel: +27 113866137; e-mail: firstname.lastname@example.org
Received 16 August, 2012
Revised 21 September, 2012
Accepted 24 September, 2012
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com).
Background: HIV-infected children are at heightened risk for severe influenza illness; however, there is no study on the efficacy or effectiveness of influenza vaccine in these children. We evaluated the safety, immunogenicity, and efficacy of nonadjuvanted, trivalent inactivated influenza vaccine (TIV) against confirmed seasonal influenza virus illness in HIV-infected children.
Methods: A double-blind, placebo-controlled trial was undertaken in Johannesburg in 2009. Four hundred and ten children were randomized to two doses of TIV or placebo 1 month apart. Nasopharyngeal aspirates obtained at respiratory illness visits were tested by influenza-specific reverse transcriptase-PCR (RT-PCR). Vaccine immunogenicity was evaluated by hemagglutinin inhibition (HAI) assay. Influenza isolates were sequenced and evaluated in maximum likelihood phylogenetic analysis.
Results: Overall, the median age of participants was 23.8 months and their median CD4% was 33.5. Ninety-two percent of enrolees were on antiretroviral therapy. Among children receiving both doses of vaccine/placebo, confirmed seasonal influenza illness occurred in 13 (all H3N2) of 205 TIV recipients and 17 (15 H3N2 and two influenza B) of 200 placebo recipients with vaccine efficacy of 17.7% (95% confidence interval <0–62.4%). The proportion of TIV recipients who seroconverted after second dose against vaccine strains of H1N1, H3N2, and influenza B were 47.5, 50.0, and 40.0%, compared to 4.7, 11.6, and 0%, respectively among placebo recipients. There were no TIV-related serious adverse events. Sequence analysis of wild-type H3N2 strains indicated drift from the H3N2 vaccine strain.
Conclusion: Poor immunogenicity of TIV, coupled with drift of circulating H3N2 wild-type compared to vaccine strain, may explain the lack of efficacy of TIV in young HIV-infected children. Alternate TIV vaccine schedules or formulations warrant evaluation for efficacy in HIV-infected children.
Antiretroviral therapy (ART)-naive HIV-infected children have an eight-fold greater risk of hospitalization due to influenza virus-associated pneumonia and trend toward higher case fatality rates (8.0%) compared to HIV-uninfected children (2.0%) [1,2]. Additionally, HIV infection is associated with prolonged shedding of influenza virus . The Advisory Committee on Immunization Practices (ACIP) recommend annual immunization of HIV-infected children with seasonal trivalent influenza vaccine (TIV) , premised primarily on the safety and immunogenicity of TIV in HIV-infected children , without any supporting efficacy or effectiveness studies. Annual TIV immunization of HIV-infected children in South Africa and other settings with a high prevalence of HIV is uncommon. Reasons for this include lack of access to TIV in public immunization programs, limited data on the burden of influenza illness in such countries, and absence of efficacy or effectiveness studies in HIV-infected children.
The primary objectives of our study were to evaluate the efficacy and immunogenicity of seasonal TIV in HIV-infected children. The study was registered under ClinicalTrials.gov, number NCT00883012.
Study design and participants
HIV-infected children aged 6–59 months attending the Perinatal HIV Research Unit Clinic in Johannesburg, South Africa were approached for study participation. Study eligibility criteria included CD4% at least 15 or receiving ART for at least 3 months prior to enrollment; parent/guardian contactable for weekly visits/calls throughout the study; and participant available to attend illness visits at the clinic. Study exclusion criteria included contraindication to influenza vaccine; presence of underlying chronic lung disease requiring treatment in the past 6 months; contraindication to intramuscular injections; known existing grade 3 or grade 4 laboratory or clinical toxicity as per Division of Acquired Imunonediciency Syndrome (Division of AIDS) toxicity tables ; previous history of receiving influenza vaccine; and systemic steroid treatment for more than 21 days in the past month.
Single-dose 0.5-ml vials of TIV (VAXIGRIP; Sanofi-Aventis; Lyon, France), per WHO recommended strain selection for the southern hemisphere for 2009, were procured commercially. Each dose contained 15 μg each of split influenza A/Brisbane/59/2007(H1N1), A/Uruguay/716/2007(H3N2), and B/Florida/4/2006. Children were randomized to receive two doses of TIV (0.5 ml if ≥36 months or 0.25 ml if younger) or equal volume of matching placebo (0.9% sterile saline) 1 month apart as recommended . The study pharmacist decanted 0.25 or 0.5 ml VAXIGRIP or 0.9% saline for the TIV and placebo group, respectively into 1 ml syringes, and dispensed according to the computer-generated randomization list. The preparations were macroscopically indistinguishable. Study drug was administered intramuscularly by the study doctor or nurse following randomization.
Participant enrollment and randomization
Study enrollment was between 18 February and 22 May 2009, that is, prior to the anticipated start of the influenza season in South Africa . Randomization lists were generated by the study statistician using a computer random number generator (SAS 9.1; SAS Institute Inc., Cary, North Carolina, USA) in random permuted group blocks of 10 with five in each study arm. Participants and study personnel, excluding the statistician and pharmacist, were blinded to treatment assignment. A subset of participants stratified by age, equal numbers below and above 36 months of age, was coenrolled in the immunogenicity cohort. Study nurses and study doctors who were blinded to the study vaccine allocation were involved in participant enrollment, vaccination, and follow-up.
Assessment of vaccine efficacy
Surveillance for influenza-like illness (ILI) was initiated from enrollment and continued until the end of the seasonal influenza season based on National Institute for Communicable Diseases (NICD) surveillance. The child follow-up time for seasonal influenza was calculated to have begun on 27 April and ended on 2 August 2009 [8,9]. Weekly short message text (SMS) reminders or telephonic contact was made with the child's caregiver to enquire about ILI symptoms. ILI was defined as an acute history (<7 days) of at least two of the following signs and symptoms: fever more than 38.5oC; myalgia or irritability; sore throat or pharyngitis; rhinorrhea and/or cough of less than 14 days of duration. Caregivers were trained to use digital thermometers for recording axillary temperature and requested to bring the child to the clinic within 48 h if there were at least two ILI criteria symptoms or other intercurrent illness.
Nasopharyngeal aspirates (NPAs) were obtained as described , when the child presented with ILI symptoms or any respiratory tract infection. NPA samples were immersed into viral transport medium and transported on wet ice to the NICD for testing within 12 h. Samples were tested for influenza A and influenza B by shell vial culture and a qualitative one-step reverse transcriptase-PCR (RT-PCR) assay. Influenza A isolates were subtyped for seasonal-H1N1 and H3N2. (CDC RT-PCR protocol for detection and characterization of influenza, CDC ref# I-007–05). Influenza identification either by shell vial culture and/or real-time RT-PCR was considered a confirmed illness.
Assessment of vaccine safety and immunogenicity
Blood samples, obtained prior to the first and 1 month following the second study vaccine dose, were collected for immunogenicity testing in a subset. Samples were centrifuged and serum archived at −70oC until shipping on dry ice to the Molecular and Virology Clinical Laboratories at the University of Colorado (Denver, USA) for hemagglutinin antibody inhibition assay (HAI).
Adverse events were actively solicited telephonically for 3 days postvaccination and parents could also contact study staff to report adverse events. Severe adverse events (SAEs) were recorded throughout the study. CD4+ cell counts and HIV PCR viral load (Roche Amplicor version 1.5; Roche Diagnostics GmbH, Mannheim, Germany) within 3 months of randomization were abstracted. CD4+ lymphocyte counts and percentage were also measured 1 month after the second dose of TIV by the panleukogating method .
Molecular characterization of the hemagglutinin gene
The HA1 region of the hemagglutinin gene was amplified by nested reverse transcription PCR assay using the Titan One Tube RT-PCR System (Roche Diagnostics GmbH) and PFx Platinum DNA polymerase (Invitrogen Corporation, Carlsbad, California, USA) reagents. PCR products were directly sequenced using the BigDye V3.1 Terminator reagents (Applied Biosystems, Foster City, California, USA). Sequence alignments were done in BioEdit Version 220.127.116.11 and evolutionary analysis and neighbor-joining phylogenetic trees analysis were done in MEGA 4 using the Maximum likelihood options with the Tamura-Nei model and 1000 bootstrap iterations as well as P-distance analysis .
Study sample size and statistical analysis
On the basis of an estimated attack rate of 20% for confirmed influenza illness in the placebo group and a power of 80% with a α of 0.05 to detect at least a 50% reduction among vaccinees, the required sample size calculated was 420. The sample size was adjusted to 550 for possible withdrawals and/or noncompliance with study protocol. A sample size of 100 was calculated for the nested immunogenicity study to demonstrate seroconversion rates of at least 40% among TIV recipients and less than 5% in placebo recipients. Enrollment into the immunogenicity subgroup was stratified to include 50 children aged 6–35 months (younger age group) and 50 aged 36–60 months (older age group).
The primary efficacy endpoint was reduction of confirmed seasonal influenza illness. Secondary outcome measures included differences for ILI and any acute respiratory illness. Vaccine efficacy was calculated using the formula of incidence rates as 1–IL/IP, (IL = the case incidence rate in TIV-vaccinated children; IP = the case incidence rate in placebo recipients). The 95% CIs were constructed and differences between the intervention arms tested at α equal to 0.05 significance level. A per-protocol analysis included children who received both doses of correct study intervention per randomization and with outcomes occurring at least 14 days following the second dose. Only the first episode of an outcome following receipt of study vaccine was included in the analysis.
Immunogenicity analysis included calculation of geometric means of the titers (GMTs) prior to the first dose and 21–35 days after the second dose of study vaccine. Treatment groups were compared with respect to the fold rise by a two-sided, two-sample t-test and the corresponding 95% confidence intervals for the ratio, all using logarithmic transformation. HAI titers of at least 1:40 if baseline titers were less than 1:10, or an at least four-fold increase in those with baseline titers at least 1:10 were considered as evidence of seroconversion. The primary immunogenicity endpoint was seroconversion rates to each of the three vaccine strains. The proportion of children with HAI at least 1:40 after second dose of vaccination was a secondary endpoint, and an exploratory analysis was undertaken to compare the proportion between groups achieving HAI threshold titers at least 1:110. Differences in proportion between study groups were compared with Kruskal–Wallis test. All statistical analyses were done using SAS software V9.1.
The study was approved by the Human Research Ethics Committee of the University of the Witwatersrand and conducted in accordance with Good Clinical Practice guidelines. Signed, written informed consent was obtained from caregiver/parent of study participants. The study was registered at ClinicalTrial.gov number: NCT NCT00883012.
Of the 410 children enrolled, 203 (98.5%) TIV recipients and 200 (98.0%) placebo recipients received both study vaccine doses (Fig. 1), at a median interval of 28 days between doses. Overall, 76% of children were aged 6–35 months. The median age, CD4+ lymphocyte count, HIV viral load, and ART regimens of the overall efficacy and immunogenicity subset cohorts are shown in Table 1. Baseline demographic and other clinical parameters were similar between study arms in the overall efficacy and immunogenicity subset cohorts (Table 1). Among TIV recipients, there were no significant changes in median CD4% or absolute CD4+ cell counts postvaccination compared to prevaccine levels in younger children (P = 0.88 and 0.11; respectively). Also, no change in median CD4+ cell count was observed in the older age group (P = 0.62), but postvaccination, CD4+% was higher (P = 0037; Table 1).
Immunogenicity of trivalent influenza vaccine
The immunogenicity per-protocol analysis was limited to 83 (86.5%) of 96 children (Fig. 1). Postvaccination, seroconversion was observed in 47.5, 50.0, and 40.0% of TIV recipients for A/Brisbane(H1N1), A/Uruguay(H3N2), and B/Florida strains, respectively (P < 0.0001 for all strains compared to placebo recipients; Table 2). Among TIV recipients, less than 40% of younger children seroconverted to any vaccine strain, and this was significantly lower for A/Uruguay(H3N2) compared to older age group (Table 2).
The proportion of TIV recipients with postvaccination HAI at least 1:40 was lower in the younger compared to older age group for A/Uruguay(H3N2) (52.2 vs. 94.1%; P = 0.005) and B/Florida (43.5 vs. 88.2%; P = 0.004; Table 3). Similarly, fewer younger TIV recipients (31.0%) had HAI at least 1:110 to A/Uruguay(H3N2) compared to older TIV recipients (52.9%; P = 0.013; Table 2). The proportion of TIV recipients with HAI at least 1:215 was less than 30% to A/Brisbane(H1N1), less than 24% to A/Uruguay(H3N2), and less than 12% to B/Florida in both age groups (Table 2). Postvaccination, GMTs were lower in the younger compared to older age group of TIV recipients for A/Uruguay(H3N2) and B/Florida (Table 2).
Efficacy of trivalent influenza vaccine against seasonal influenza illness
Investigation for influenza virus occurred in 123 children who were investigated on 144 illness occasions, including 74 (51.4%) which fulfilled ILI criteria (Table 3). Multiple illness visits spaced at least 7 days apart were undertaken in 20 children, including one with three illness visits. The median age of children was 18.8 months (range 6–54.6) for ILI and 20.9 months (range 6–54.6) for confirmed influenza illness. There were 19 episodes of confirmed influenza illness among TIV recipients and 21 in placebo recipients. The dominant strain of influenza virus identified was H3N2 (37 of 40 cases). Two TIV recipients, aged 13.5 and 21.7 months with CD4+% of 27.6 and 36.8 and HIV viral load of less than 40 and more than 750 000 copies/ml at enrollment, respectively, experienced two episodes of confirmed H3N2 illness spaced 13 and 38 days apart.
The overall incidence (per 100 child-weeks) was 2.6 (95% CI 2.2–3.1) for medically attended respiratory illness, including 1.3 (95% CI 1.1–1.7) for ILI and 0.7 (95% CI 0.5–1.0) for confirmed influenza illness (Table 3). The incidence rates of ILI or confirmed influenza illness did not differ between study arms in the intent-to-treat or per-protocol analysis (Table 3). There were three TIV recipients in the immunogenicity subset with confirmed H3N2 influenza illness, all of whom received both TIV doses and were on ART. These children were 21.4, 25.0, and 54.6 months of age and had CD4+% of 24.3, 31.3, and 31.4, respectively. Two children less than 36 months failed to mount an immune response to any vaccine strain, although postvaccination HAI titers were 1:40 for each vaccine strain in the older child.
There were one TIV and two placebo recipients hospitalized for pneumonia during the influenza season, none of whom tested positive for influenza virus. One death occurred in a placebo recipient outside of a health facility during the seasonal influenza period, which was attributed to pneumonia but not tested for influenza virus.
Phylogenetic analysis on 21 randomly selected wild-type H3N2 viruses from study participants formed two clusters with a mean protein distance of 1.2 and 2.6%, respectively, to the vaccine strain (Supplemental digital material, http://links.lww.com/QAD/A267). Site-by-site amino acid analysis of the H3N2 viruses (Fig. 2) showed evidence of drift in reference to the A/Uruguay(H3N2) vaccine strain, as indicated by mismatched amino acid changes mapped to the immunodominant epitopes A (S138A), B (K158N; N189K; P194L), and D (K173Q; T212A).
Safety of trivalent influenza vaccine
There were no grade 3 or above solicited adverse events following either the first or second dose of study vaccine. The only solicited adverse events documented among TIV recipients within 3 days of either dose of vaccine were pain at site of injection (n = 1; 2.3%), fever at least 37.5oC (n = 2; 4.2%), induration at injection site (n = 1; 2.3%), and weakness (n = 2; 4.5%).
To our knowledge, this is the first randomized-controlled study which evaluated the efficacy of TIV in HIV-infected children. In our study of children mainly 6–35 months of age, who are at heightened risk of severe influenza illness independent of HIV infection , TIV vaccination did not prevent confirmed seasonal influenza illness or ILI. The lack of efficacy was in part corroborated by the poor immunogenicity of TIV against the dominant wild-type circulating strain, particularly in the younger age group (32.0% seroconversion).
Possible reasons for the lack of efficacy in our study include those which are inherent to any study evaluating TIV vaccine efficacy. These include the unpredictability of the severity of the influenza virus which emerges and possible vaccine strain mismatch to the wild-type strain. Genotypic analysis of H3N2 isolates from our study revealed only a 1.2% change in mean protein distance compared to A/Uruguay-like virus. These amino acid changes, however, affected key positions in three hemagglutinin epitopes (A, B, and D). The changes in epitopes A (S138A) and B (P194L) corresponded to positions that form part of the receptor-binding site . Immunodominant epitopes A and B induce high efficiency neutralizing antibodies. Whereas single epitope changes for A or B are associated with minor antigenic drift, mutations resulting in two or more changed epitopes as in our study are considered as major antigenic drift which necessitates selection of a new vaccine strain . HAI analysis of the wild-type H3N2 strains was not possible due to the phenotypic characteristic of recent H3 strains which do not hemagglutinate red blood cells from various species . A reference serum to A/Uruguay(H3N2)(2007), however, was negative in HAI assays against A/Perth/16/2009, suggesting a similar result could be expected for wild-type strains with the same mutations at receptor-binding site positions 138 and 194 .
The lack of efficacy may also be attributed to the poor immunogenicity of TIV, particularly in younger HIV-infected children. Although we did not enroll a control group of HIV-uninfected children, the seroconversion rates in the younger age group were lower compared to the 77.8% (H3N2) to 86.1% (Influenza/B) among healthy Canadian children aged 6–35 months , in whom an identical TIV formulation and dosing concentration was evaluated. The seroconversion rates in the Canadian study were also generally higher compared to our study's older age group. The impaired immune responses to TIV in our study may be due to HIV-induced impaired B-lymphocyte function, required for immune responses to TIV, which persist even following immune reconstitution with ART [17–19]. Impaired memory B-cell response to TIV in HIV-infected individuals has been attributed to deficiencies in serum and B-cell activating factor and APRIL (a proliferating-inducing ligand) and alteration in their receptors .
Traditionally HAI titers at least 1:40 have been used as a putative measure of relative protection against influenza illness in adults [20,21]. The relevance of this threshold in children is unclear [22,23]. Additionally, a HAI titer of 1:40 is associated with only 50% protection against influenza illness in adults [20,23], despite the likely presence of underlying cell-mediated immunity to influenza induced by previous exposure to influenza antigens from vaccination or from circulating wild-type influenza-virus. This underlying cell-mediated immunity is associated with cross-protection against different influenza strains , and boosting thereof by vaccination may contribute towards enhancing the efficacy of TIV in adults, which may also in-part mitigate the effect of any mismatch between the vaccine and circulating wild-type influenza strains. Although cell-mediated immune responses are induced in young children immunized with live-attenuated influenza vaccine (LAIV), such responses are less evident with TIV in the absence of previous exposure to related vaccine strains . In addition, young children are more likely to be influenza-naive and consequently may require higher HAI titers, although vaccine strain mismatch may be more relevant in them compared to that in adults. Black et al. modeled that in children, HAI titers of at least 1:110 and at least 1:215 were predictive of 50 and 70% protection, respectively. In our study, an exploratory analysis identified only 13% of younger and 52.9% of older TIV recipients achieved HAI titers at least 110 to A/Uruguay (H3N2), and less than 30% in both age groups had titers at least 1:215 for any vaccine strain. The one vaccine failure due to H3N2 involved a 54.6-month-old child in our study, who had postvaccination H3N2-HAI titer of 1:40.
Most other immunogenicity studies on influenza vaccine in HIV-infected children have involved older HIV-infected children and adolescents [25–30]. Some of these studies preceded management of HIV-infected children with combination, triple ART [25,26,28], and more recently have focused on children/adolescents on ART who were immunologically reconstituted and virologically suppressed [29–31]. Among HIV-infected children on ART, immune responses to TIV correlated with immunological status prior to vaccination, with moderate-to-severe immunocompromised children benefiting from a second dose of vaccine . In addition, the magnitude of immune response and proportion of children with presumed seroprotective levels were lower than in healthy controls for at least two vaccine strains .
The lack of efficacy in our study was surprising, considering the 75% efficacy reported in the same setting among HIV-infected adults despite only modest seroconversion rates to TIV (47.4–60.8%) . In addition to the slightly lower seroconversion rates to TIV in this study (40–50%), other reasons for the difference in TIV efficacy between HIV-infected adults and children may include that the adults were possibly more likely to have established underlying cell-mediated immunity to influenza virus because of more frequent exposure to wild-type virus over their life time. This would have possibly enhanced their protection against influenza illness because of the role of cell-mediated immunity in clearing influenza infection as well as conferring some protection against influenza strains which are heterologous to the vaccine strain .
Recent studies have evaluated alternate influenza vaccine formulations, such as virosomal adjuvant vaccines [33,34], MF59-adjuvant and ASO3-adjuvant influenza vaccine, and LAIV [35–40], for safety and immunogenicity in HIV-infected children. Palma et al. reported immunogenicity of MF59-adjuvanted monovalent H1N1 influenza vaccine in HIV-infected children following a single dose of vaccine, in whom seroconversion rate was 60%, but less than that in healthy controls (82%). In healthy children aged 6–72 months, the MF59-adjuvanted influenza vaccine was 81% more efficacious than unadjuvanted TIV. This included 79% efficacy against confirmed influenza illness in children aged 6–35 months and 92% efficacy in children aged 36–72 months, which was approximately double the efficacy observed for nonadjuvanted TIV .
Limitations of our study include being a single-center study because of it primarily been investigator-funded. Furthermore, the evaluable sample size (n = 403) only had 40% power to detect a 50% reduction in confirmed influenza based on the 10% attack rate observed among placebo recipients. The sample size was, however, sufficient to detect at least 73% vaccine efficacy at 80% power based on the observed attack rate. Although the study did not complete enrollment of the targeted 550 participants prior to the peak of the influenza season, this was offset by only 4.1% (n = 17) of enrollees, rather than the projected 20%, being lost to follow-up or withdrawn. A further limitation of our study is that it was conducted over a single influenza season. The study is, therefore, unable to definitively conclude the relative roles of poor TIV immunogenicity in younger children or antigenic drift of the circulating wild-type H3N2 away from the vaccine strain as being responsible for the lack of efficacy observed against confirmed influenza illness. Also, very few (<18%) of the children in our study were breastfed at any stage. It is possible that predominantly breastfed children may have mounted better immune responses, as breastfeeding contributes to boosting of the infant adaptive and innate immune system .
The results from our study do not support current recommendations for immunization of young HIV-infected children with nonadjuvanted TIV, even if on ART. We propose that further multicentered controls studies, which include a placebo arm and which are powered to investigate efficacy against confirmed influenza illness and not only immunogenicity, are required. Such studies should consider evaluating higher strength doses of TIV in young children, as well as the possible roles of LAIV and adjuvanted TIV in protecting HIV-infected children against influenza illness.
The authors would like to thank all the children and their parents for their participation in this study. In addition, the support of the nursing, pharmacy, and general staff at Perinatal HIV Research Unit and data clerks at the Respiratory and Meningeal Pathogens Research is acknowledged.
S.A.M. and A.V. contributed to the study conceptualization and design. First draft of the article was cowritten by S.A.M. and A.V. S.D., H.C., E.L., and T.T. were involved in participant follow-up and management. M.V. and F.T. were responsible for laboratory testing of influenza virus. A.W. was responsible for doing the hemagglutinin inhibition tests. C.L.C. was involved in protocol development and study logistics. M.V. and F.T. made input on the article sections on genotypic characteristic of the wild-type influenza virus, and A.W. on the immunogenicity data. All the authors critically reviewed the article and contributed to the final draft.
The study was funded in part through an unrestricted grant from Secure the Future Fund. The rest of the study, including vaccine procurement, was investigator-funded. Secure the Future did not have any input into the study design, data analysis, or write-up of the article.
Conflicts of interest
There are no conflicts of interest.
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