Next Article in Journal
Monitoring the Risk of Type-2 Circulating Vaccine-Derived Poliovirus Emergence During Roll-Out of Type-2 Novel Oral Polio Vaccine
Next Article in Special Issue
Neuraminidase Antibody Response to Homologous and Drifted Influenza A Viruses After Immunization with Seasonal Influenza Vaccines
Previous Article in Journal
Turning Cancer Immunotherapy to the Emerging Immune Checkpoint TIGIT: Will This Break Through the Limitations of the Legacy Approach?
Previous Article in Special Issue
Safety, Immunogenicity and Protective Activity of a Modified Trivalent Live Attenuated Influenza Vaccine for Combined Protection Against Seasonal Influenza and COVID-19 in Golden Syrian Hamsters
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Vaccines
Volume 12
Issue 12
10.3390/vaccines12121307
vaccines-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

The Impact of Obesity on Influenza Vaccine Immunogenicity and Antibody Transfer to the Infant During Pregnancy

by
Michelle Clarke
1,2,
Suja M. Mathew
1,2,
Lynne C. Giles
3,
Ian G. Barr
4,
Peter C. Richmond
5,6 and
Helen S. Marshall
1,2,*
1
Women’s and Children’s Health Network, North Adelaide, SA 5006, Australia
2
The Robinson Research Institute, Adelaide Medical School, The University of Adelaide, Adelaide, SA 5005, Australia
3
School of Public Health, The University of Adelaide, Adelaide, SA 5005, Australia
4
WHO Collaborating Centre for Reference and Research on Influenza, The Peter Doherty Institute, Melbourne, VIC 3000, Australia
5
Discipline of Pediatrics, University of Western Australia, Perth, WA 6009, Australia
6
Wesfarmers Centre of Vaccines and Infectious Diseases, Kids Research Institute of Australia, Perth Children’s Hospital, Perth, WA 6009, Australia
*
Author to whom correspondence should be addressed.
Vaccines 2024, 12(12), 1307; https://doi.org/10.3390/vaccines12121307
Submission received: 15 October 2024 / Revised: 7 November 2024 / Accepted: 18 November 2024 / Published: 22 November 2024
(This article belongs to the Special Issue The Recent Development of Influenza Vaccine: 2nd Edition)
Browse Figures
Versions Notes

Abstract

:
Background/Objectives: Influenza vaccination is recommended for pregnant women, offering the dual benefit of protecting pregnant women and their newborn infants against influenza. This study aimed to investigate the impact of body mass index (BMI) on influenza vaccine responses in pregnant women and their newborns. Methods: Participants included pregnant women attending the Women’s and Children’s Hospital in South Australia between 2018 and 2021. Maternal blood samples were collected prior to and at 1 and 6 months post-influenza vaccination to measure antibody responses by hemagglutination inhibition (HI) assay. Cord blood samples were also collected. The percentages of participants achieving HI titre ≥40 were compared between obese and non-obese groups. Results: A total of 73 women were enrolled and received quadrivalent influenza vaccination at a mean age of 32 years (range 21–44 y) and median gestation of 24 weeks (range 11–37 weeks). BMI at vaccination was ≥30 kg/m2 for 21/73 women (29%). Most pregnant women demonstrated antibody titres ≥ 40 to all four influenza vaccine strains at 1 month post-vaccination regardless of BMI category (BMI ≥ 30 kg/m2: 19/20; 95% vs. BMI < 30 kg/m2: 47/49; 96%). At 6 months post-vaccination, 12/17 (71%) obese women compared to 36/43 (84%) non-obese women (p = 0.25) maintained HI titres ≥ 40. Cord blood serology showed HI titres ≥ 40 for 11/17 (65%) infants born to mothers with BMI ≥ 30 compared to 30/35 (86%) infants delivered by mothers with BMI < 30 kg/m2. Conclusions: A high BMI did not impair influenza vaccine antibody responses in pregnant women at 1 month post-vaccination. However, at 6 months post-vaccination, and in the cord blood samples, the percentages maintaining HI titre ≥ 40 were lower for obese women than for non-obese pregnant women.

1. Introduction

Influenza is a highly contagious respiratory viral disease that can affect people of all ages worldwide. Whilst seasonal variations are common, it is estimated that one in five children and one in ten adults are infected with influenza annually [1]. Although most people recover without requiring medical attention, pregnant women, very young infants and people with obesity are some of the risk groups that are particularly vulnerable to more severe illness following influenza infection [2,3,4,5,6,7,8]. In Australia, and many other countries, influenza vaccination is recommended during pregnancy for the dual benefit of protecting mothers and their infants from severe influenza illness and its complications [8,9,10]. Given that influenza vaccines are only licenced for infants from 6 months of age, maternal influenza vaccination during pregnancy is currently the best strategy available for protecting young infants. Infants are at risk of complications from influenza infection and have the highest age-specific influenza hospitalisation rates [8,11,12]. Young infants therefore rely on passive antibody transference from their mother during pregnancy to provide protection against influenza infection.
Pregnant women are also at greater risk of more severe influenza illness than non-pregnant women [4,6]. Furthermore, obesity is recognised both as a risk factor for more severe influenza infection [2,3,7,13] and as a potential mediator of impaired vaccine responses [14,15,16,17,18,19]. To date, very few studies have examined the association between obesity and influenza vaccine responses in pregnant women [20,21], although a study in non-pregnant adults found that obesity was associated with a more rapid decline in antibodies at 12 months post trivalent influenza vaccination [17]. There are no published studies comparing influenza antibody titres in cord blood in regard to obese vs. non-obese women receiving influenza vaccination during pregnancy. More than 30% of Australian females are living with obesity at present [22]. Globally, in 2022, an estimated 16% of adults are living with obesity; however, this varies greatly by region, with lower rates of adult females living with obesity being seen in countries such as Vietnam, Japan and Ethiopia (<5%) and rates higher than 30% being seen in countries such as USA (43%), South Africa (46%) and New Zealand (35%) [23], Therefore, understanding whether obese pregnant women can develop adequate influenza antibody vaccine responses, and maintain and transfer adequate influenza-specific antibodies to their infants, is important for ensuring that the current vaccine programme is providing optimal protection for pregnant women and their young infants irrespective of their BMI.

2. Materials and Methods

2.1. Study Procedures and Participants

This prospective cohort study was conducted at a tertiary maternity and paediatric hospital in South Australia between August 2018 and May 2022. Pregnant women attending antenatal services were approached by research nurses and invited to participate if they met the study eligibility criteria. From May 2020, printed flyers summarising the study with an opportunity to register interest were provided in antenatal packs given to women attending the antenatal services, as face-to-face recruitment was restricted due to the COVID-19 pandemic. Inclusion criteria required participants to be at least 18 years of age, have a sufficient enough understanding of the English language to provide valid consent and to be willing to receive a seasonal influenza vaccination. Women with significant medical conditions, including insulin-dependent diabetes, immunosuppressive conditions or requiring immunosuppressive medication, were excluded. In addition, women with any contraindication to vaccination, or those who had received any immunoglobulin therapy, blood or blood products or influenza vaccination within the previous six months, were excluded.
After written informed consent, pregnant women were administered a 0.5 mL dose of a licenced, seasonal quadrivalent inactivated influenza vaccine (Fluquadri®, Sanofi-aventis, Macquarie Park, Australia). If the participant was also eligible for a dTpa vaccine (gestation > 20 weeks) and had not already received a pertussis-containing vaccine during their current pregnancy, a dose of Adacel® (Sanofi-aventis, Macquarie Park, Australia) was also administered. Vaccines were administered by Immunisation Nurses or medical officers according to the Australian Immunisation Handbook recommendations. Participants’ heights and first-trimester weights were assessed by a study investigator at the first study visit. BMI was used to classify participants as either obese (≥30 kg/m2) or non-obese (<30 kg/m2). Clinical and demographic information, including maternal age, country of birth, gestational weeks at vaccination, prior influenza vaccination history and laboratory-confirmed respiratory illnesses within the previous 12 months, were also recorded. Serious adverse events were collected during the study via participant diaries and a review of medical records following study completion.
Whilst the study aimed to enrol 150 participants, institutional rules during the COVID-19 pandemic impacted study recruitment, impacting the overall power of the study. The COVID-19 pandemic also affected retention of study participation through to study completion. Enrolled participants had a blood sample collected at baseline (prior to vaccine administration) at 1 month following vaccination and again at approximately 6–7 months following vaccination (post-delivery). In addition, cord blood was collected (where possible) at the time of delivery to measure antibody responses to the vaccines administered. Pre-vaccination blood samples were collected from 73 enrolled participants, of whom 21 (29%) were obese. Post-vaccination blood samples were collected from 69 participants at 1 month post-vaccination and at 60 participants at 6 months post-vaccination. Cord blood samples were collected from 52 (71%) participants at delivery (see Figure 1, Table 1).

2.2. Serology and Immunogenicity Assessment

Serum samples were sent to the WHO Collaborating Centre for Reference and Research on Influenza (Melbourne, Australia) to measure influenza antibody titres by hemagglutination inhibition (HI) assay according to the WHO method [24]. HI antibody titrations of the participant serum samples were all run in the same assay for each virus tested to reduce assay variability. Any sera featuring titres ≥ 1280 were re-titrated to obtain an endpoint titre. HI results that were negative (i.e., agglutination apparent at <1:10 dilution) were assigned a titre of 5 for subsequent calculations. Post-infection ferret antisera raised to the appropriate wild-type virus for each type/subtype/lineage vaccine virus tested were used as positive controls in all assays and compared with previously obtained titres. Viruses used for HI analysis were matched to the vaccines received and included A/H1N1, A/H3N2, B/Victoria and B/Yamagata viruses. Additionally, 1% (v/v) Turkey red blood cells were used in all HI assays. HI titres ≥ 40 were considered seroprotective (SP).

2.3. Design and Statistical Analysis

The primary aim of the study was to compare the proportion achieving seroprotection in women with pregnancy BMI < 30 kg/m2 to those with BMI ≥ 30 kg/m2) to determine whether the proportions were different between the groups. Assuming a 1:2 ratio of obese to non-obese participants (based on population obesity characteristics), and with the assumption that the proportion of non-obese participants who fail to achieve seroprotective titres to at least 1 strain following influenza vaccination is 0.2 (20%), if the true failure rate for obese participants is 0.5 (50%), 33 obese and 66 non-obese participants were required to be able to reject the null hypothesis with 80% power.
The proportions of obese vs. non-obese pregnant women in the population with HI titres ≥ 40 units were compared using a z-test of two proportions for each influenza strain individually and for the composite of all four influenza vaccine strains following influenza vaccination. Mann–Whitney tests were used to compare Geometric Mean Antibody Titres (GMTs) and GMT Ratios (GMTRs) between obese and non-obese groups at each timepoint. A multivariable log binomial model was used to estimate the risk of seroprotection against all four strains for obese compared to non-obese pregnant women at 1 and 6 months post-vaccination and at delivery. The models were adjusted for the trimester during which vaccination was given and for coadministration of a pertussis vaccine. Variables for inclusion in the multivariable model were prespecified and selected for their potential impact on the outcome, recognising the limitations brought about by the sample size. Statistical significance was assessed at the 0.05 level using two-sided tests. Effect estimates are presented with their 95% confidence intervals.
This study was approved by the Women’s and Children’s Health Network Human Research Ethics Committee (HREC/17/WCHN/63) and registered at Clinicaltrials.gov (NCT03457194) prior to recruitment.

3. Results

3.1. Participants

A total of 74 pregnant women consented to participating in the study, with one participant withdrawing prior to vaccination. Of the 73 participants who were consented and vaccinated, 52 (71%) had a pre-vaccination BMI < 30 kg/m2 and 21 (29%) had a pre-vaccination BMI ≥ 30 kg/m2 (Figure 1). Otherwise, the demographic characteristics and vaccination histories were similar between groups There were no underweight participants (BMI < 18 kg/m2) included in the study. There were 26 women with a BMI of between 18 and 24.9 kg/m2 and 26 women with a BMI of between 25 and 29 kg/m2. For the obese group, 13 had a BMI of between 30 and 34.9 kg/m2, four women had a BMI of between 35 and 39.9 kg/m2 and four women had a BMI greater than 40 kg/m2. The highest BMI was 43.7 kg/m2.
The mean age of enrolled participants was 32.5 years (SD 4.6 years; range 21–44 years). The mean gestation at vaccination was 23.6 weeks (SD 7.1 weeks, range 11–37 weeks). Most participants were born in Australia (71%) and had previously received an influenza vaccine (74%). The mean interval between vaccination and sample collection at each timepoint was similar for both groups (Table 1).

3.2. Vaccine Responses: Geometric Mean Titres

The pre-vaccination Geometric Mean HI antibody titres were similar for obese vs. non-pregnant women for both influenza A/H3N2 and influenza A/H1N1; however, obese pregnant women had lower mean influenza B GMTs prior to vaccination, particularly for B/Victoria (mean obese 27.8, 95% CI 17.9–43.3 vs. mean non-obese 49.5, 95% CI 38.7–63.3, p = 0.03). At 1 month post-vaccination, both obese and non-obese pregnant women groups demonstrated 2–10-fold increases in GMTs for each of the four influenza strains (A/H3N2, A/H1N1, B/Yamagata and B/Victoria), with the highest rise in GMTs being evident for A/H1N1 (an approximately 10-fold increase from baseline for the obese group and a 6-fold increase for the non-obese group).
Whilst antibody titres declined by 6 months post-vaccination, they remained above pre-vaccination levels for all four influenza antigens. Cord blood samples also demonstrated elevated HI antibody titres for all influenza antigens for both obese and non-obese pregnant women compared with baseline antibody titres (Table 2, Figure 2).

3.3. Impact of Coadministration of Adacel

Almost half of the participants had Adacel coadministered at the time of their influenza vaccination (32/73, 44%) (Table 1). There were no significant differences in the Geometric Mean HI Titres to any of the four influenza vaccine strains at any of the post-vaccination timepoints (1 m, at delivery and at 6 m) for women who received a FluQuadri vaccine alone or who were coadministered with Adacel (Supplementary Table S1).

3.4. Seroprotection

For influenza vaccines, one evaluation criterion used to assess vaccine immunogenicity is the proportion of recipients who achieved a HI titre of ≥40 at 1 month post-vaccination [25]. This threshold is estimated to confer approximately 50–70% protective efficacy against clinical symptoms of infection. Over three-quarters of the non-obese pregnant women had antibody titres ≥ 40 to all four influenza vaccine strains prior to receiving the vaccine. Similar proportions were evident for the obese vs. non-obese pregnant women for A/H3 (71% vs. 75%, p = 0.75), and A/H1 (81% vs. 75%, p = 0.59); however, obese pregnant women appeared to have slightly lower pre-vaccination titres as compared to non-obese pregnant women for B/Yamagata (76% vs. 92%, p = 0.06) and B/Victoria (48% vs. 79%, p < 0.01) (Table 2).
At 1 month post-vaccination, the proportion with seroprotective antibody titres was greater than 95% for both obese and non-obese groups for each of the four influenza strains. Seroprotective antibodies were sustained over 6 months for both obese and non-obese groups for both the influenza A/H3N2 (94% vs. 95%) and A/H1N1 (100% vs. 100%) strains. A high proportion of cord blood samples from both obese and non-obese pregnant women also demonstrated seroprotective antibody titres in regard to A/H3N2 (88% vs. 94%) and A/H1N1 (100% vs. 100%). For influenza B strains, however, although the proportion of samples with seroprotective antibody titres remained high, it was lower for the obese group compared to the non-obese group for both the cord blood samples (B/Vic: 76% vs. 91%, p = 0.14; B/Yam: 94% vs. 100%, p = 0.15) and the 6-month-post-vaccination samples (B/Vic: 82% vs. 88%, p = 0.54; B/Yam:88% vs. 100%, p = 0.02).

3.5. Predictors of Optimal Seroprotective Responses

Optimal seroprotective response was defined as a HI Titre ≥ 40 for all four influenza strains (A/H3N2, A/H1N1, B/Yamagata and B/Victoria).
Almost half of the enrolled participants (34/73; 22%) had pre-vaccination HI titres ≥ 40 for all four of the influenza strains tested (A/H1N1, A/H3N2, B/Yamagata and B/Victoria). At 1 month post-vaccination, this proportion increased to 96% (n = 66/69) of participants with seroprotective antibody titres to all four vaccine component antigens, indicating robust immediate vaccine responses regardless of BMI group (Table 3). At 6 months post-vaccination, and for cord blood samples, a lower proportion had HI titres ≥ 40 for all four influenza vaccine strains for the obese vs. non-obese group (6 m: 71% vs. 84%, p = 0.32; cord: 65% vs. 86%, p = 0.14). In the multivariable log-binomial models adjusting for trimester at vaccination and coadministration of a pertussis vaccine, obese pregnant women had a 25% lower risk regarding maintaining seroprotective antibody titres through to 6 months post-vaccination for all four influenza strains compared to non-obese women (aRR 0.75, 0.53–1.08, p = 0.13). Similarly, obese pregnant women had a 25% lower risk for seroprotective antibody titres for all four influenza strains in their cord blood samples compared to non-obese pregnant women (aRR 0.75, 0.54–1.05, p = 0.10) (Table 3).

3.6. Safety

There were 15 serious adverse events (SAEs) reported for 10 maternal participants during their study participation. All SAEs were deemed unrelated to the study vaccines following review and investigation by a study medical officer. SAEs were reported for 9/52 participants in the non-obese group (17%) vs. 1/21 (5%) in the obese group (p = 0.26).

4. Discussion

Both obese and non-obese pregnant women achieved robust antibody responses to all influenza vaccine strains at 1 month post-vaccination, with 95–100% of vaccine recipients achieving HI titres of ≥40. However, our study suggests that obese pregnant women were less likely to maintain seroprotective antibody levels at the 6-month-post-vaccination sample timepoint in regard to all four influenza vaccine antigens compared with non-obese pregnant women. Similarly, cord blood samples collected from obese pregnant women were less likely to have seroprotective antibody levels against all four influenza vaccine antigens compared with cord blood samples from non-obese pregnant women.
For influenza A, almost all participants achieved, maintained to 6 months, and adequately transferred antibodies to their infant regardless of BMI category. For influenza B lineage strains, whilst the obese group had lower GMTs for both B/Yamagata and B/Victoria lineage antibodies than the non-obese group across all timepoints (baseline, 1 m, cord and 6 m), the proportion achieving seroprotective antibody titres (HI ≥ 40) at 1 m, cord sample and 6 m post-vaccination remained above 75%. For all influenza strains, and at each sample timepoint, the proportion of participants with seroprotective HI titres remained above the 70% threshold specified by the European Agency for the Evaluation of Medicinal Products (EMEA) as one of the criteria for serological assessment of influenza vaccine response that was previously used by the agency [25]. A serum HI antibody titre ≥40 has been considered to be associated with >50% reduction in the risk of subsequent influenza disease or infection [26,27,28].
Our study results support the findings of other published studies which indicate that obesity does not significantly impair the ability to achieve seroprotective antibody responses following influenza vaccination in pregnant [20,21] or non-pregnant adults [29,30,31] at 1 month post-vaccination, adding the additional information that these robust antibody responses are well maintained through to 6 months post-vaccination and are adequately transferred to the foetus.
GMTs and seroprotective antibody levels were lower for influenza B strains at baseline timepoints for obese vs. non-obese pregnant women, which may suggest more rapid waning of previously acquired antibodies in obese vs. non-obese groups, but this was not observed for influenza A strains. This may be due to the higher frequency of repeat exposure to circulating influenza A viruses in the community compared with influenza B strains allowing for the natural boosting of antibodies to mask any impact of the more rapid waning of antibodies in obese persons. A study from Sheridan et al. assessing obesity and influenza vaccine responses in a non-pregnant adult population showed that obese populations had a more rapid waning of vaccine-induced antibodies at 12 months post-vaccination compared to non-obese vaccine recipients [17], and it also demonstrated that T-cell activation was more impaired in obese individuals compared with healthy weight individuals. Evidence for an association between obesity and the more rapid waning of vaccine responses has also been shown for COVID-19 vaccines [32,33], with authors suggesting that increased glycosylation of antibodies or a lack of high-affinity antibodies may be implicated in the impaired longevity of vaccine antibody responses in obese persons.
Whilst our data showed adequate seroprotective titres amongst obese and non-obese pregnant women at each timepoint, there was some evidence that antibodies waned more quickly in obese vs. non-obese participants for some influenza strains, although this was not demonstrable as being statistically significant with our sample size. This finding may have implications for obese women vaccinated in early pregnancy. In Australia, influenza vaccination is recommended at any stage of pregnancy, and a recent cohort study found that 25% of women were vaccinated in their first trimester [34]. We have also previously shown that influenza B strains may cause more severe illness in young children [35]; therefore, determining optimal maternal vaccination timing to provide adequate protection against both influenza A and influenza B is an important public health strategy. Recent surveillance, however, suggests that B/Yamagata lineage influenza strains have disappeared globally since the COVID-19 pandemic [36]. The World Health Organisation has therefore advised that the B/Yamagata lineage antigen is no longer warranted for inclusion in 2024–2025 influenza vaccines, but the B/Victoria lineage viruses have continued to circulate [37].
This study does have several limitations. Firstly, the reduced sample size achieved relative to the planned sample size restricted the variables that could be considered in adjusted models; therefore, the study was underpowered in regard to detecting the anticipated differences between groups. Small but clinically important differences between obese and non-obese groups may be difficult to demonstrate without a larger sample size. In addition, the participants enrolled were not a true random sample of obese and non-obese pregnant women. Given these limitations, the study findings may not be generalisable to the wider population of pregnant women and larger studies would be required to provide further evidence regarding the role of obesity in vaccine antibody longevity.
Whilst obesity is one factor that has been implicated in impaired immunogenicity, many other host and environmental factors may also impact the immunogenicity of influenza vaccines [38,39]. While our regression models adjusted for trimester at vaccination and coadministration of pertussis vaccination, other important potential confounding variables, such as vaccination history, other health conditions, microbiome and genetics, may also influence vaccine responses and were not assessed or controlled for in our study. Furthermore, more than 75% of our participants had received a prior influenza vaccine and had seroprotective titres at baseline. Therefore, our study findings may not be generalisable to vaccine-naïve populations.
Additionally, this study only assessed humoral immunity and did not measure potential differences in cell-mediated immunity that may play an important role in protection against influenza. It has been increasingly recognised that, whilst the HI titre ≥ 40 threshold has been the most commonly accepted correlate for protection, it may not apply equally to all groups and other measures of protection are also important to consider [40,41]. Finally, it is important to note that equivalent HI titres may not translate to equivalent protection against influenza illness for groups with and without obesity. A large prospective observational study in adults who received trivalent influenza vaccine showed that vaccinated obese participants had twice the risk of influenza or influenza-like illness compared with vaccinated healthy weight participants despite similar immunogenicity [42]. Therefore, it is important to continue to monitor vaccine efficacy to ensure that current influenza vaccine programmes and policies adequately protect obese and non-obese pregnant women and their newborns. Obese pregnant women vaccinated in early pregnancy may benefit from a second influenza vaccination during pregnancy to ensure optimal seroprotection against influenza for their newborns; however, larger studies are required to evaluate this. Additional studies assessing immunogenicity at 12 months post-vaccination in obese vs. non-obese individuals would be useful to determine whether twice yearly influenza vaccinations may provide additional benefits for people living with obesity.

5. Conclusions

In conclusion, our study was able to demonstrate that, whilst obesity did not impact the attainment of seroprotective antibody titres at 1 month post-vaccination, there was an indication that the maintenance of antibodies for 6 months and placental transfer of influenza antibodies may be lower for obese compared to non-obese pregnant women for some influenza strains. Future studies with a larger cohort are required to understand whether the current vaccine policy is adequate at a population level for protecting obese pregnant women and their infants.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/vaccines12121307/s1, Table S1: Antibody responses to influenza vaccine in pregnant women by vaccines received (FluQuadri alone vs FluQuadri + Adacel).

Author Contributions

Conceptualisation, M.C. and H.S.M.; formal analysis, M.C. and L.C.G.; funding acquisition, M.C. and H.S.M.; investigation, M.C. and S.M.M.; methodology, M.C., S.M.M., L.C.G., I.G.B., P.C.R. and H.S.M.; project administration, M.C.; supervision, L.C.G., P.C.R. and H.S.M.; writing—original draft, M.C.; writing—review and editing, M.C., S.M.M., L.C.G., I.G.B., P.C.R. and H.S.M. All authors have read and agreed to the published version of the manuscript.

Funding

This investigator-sponsored study received funding from Sanofi (ISS FLU00063) and the Robinson Research Institute (COVID-19 impact grant). The vaccines used in this study (FluQuadri and Adacel) were provided by Sanofi. The WHO Collaborating Centre for Reference and Research on Influenza, Melbourne, is supported by the Australian Government Department of Health and Aged Care. Professor Helen Marshall is supported by an NHMRC Fellowship.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and the National Statement on Ethical Conduct in Human Research. The study was approved by the Women’s and Children’s Health Network Human Research Ethics Committee (HREC/17/WCHN/63) on 2 May 2017.

Informed Consent Statement

Informed consent was obtained from all participants involved in the study.

Data Availability Statement

De-identified data presented in this study are available on request from the corresponding author.

Acknowledgments

We gratefully acknowledge the study participants for their involvement and the staff of the Vaccinology and Immunology Research Trials Unit for their expertise and assistance with study procedures. We would also like to acknowledge the expertise and support from the WHO Collaborating Centre for Reference and Research on Influenza for performing the Hemagglutination Inhibition Assays, particularly Heidi Peck and Malet Aban.

Conflicts of Interest

The funders had no role in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. M. Clarke, H. S. Marshall, P. C. Richmond, and S. M. Mathew are investigators involved in clinical vaccine trials, and their institutions receive research grants for investigator-led vaccine research/sponsored clinical vaccine trials from pharmaceutical industry companies, including GSK, Pfizer, Sanofi and Merck. None of the authors received any personal payments from the industry in relation to this research. Ian G. Barr has shares in an influenza vaccine producing company. The WHO CCRRI receives funds from Seqirus Limited and from the IFPMA for its influenza surveillance activities. Lynne C. Giles has no conflicts of interest to declare.

References

  1. Somes, M.P.; Turner, R.M.; Dwyer, L.J.; Newall, A.T. Estimating the annual attack rate of seasonal influenza among unvaccinated individuals: A systematic review and meta-analysis. Vaccine 2018, 36, 3199–3207. [Google Scholar] [CrossRef] [PubMed]
  2. Fezeu, L.; Julia, C.; Henegar, A.; Bitu, J.; Hu, F.B.; Grobbee, D.E.; Kengne, A.-P.; Hercberg, S.; Czernichow, S. Obesity is associated with higher risk of intensive care unit admission and death in influenza A (H1N1) patients: A systematic review and meta-analysis. Obes. Rev. Off. J. Int. Assoc. Study Obes. 2011, 12, 653–659. [Google Scholar] [CrossRef] [PubMed]
  3. Mertz, D.; Kim, T.H.; Johnstone, J.; Lam, P.P.; Science, M.; Kuster, S.P.; Fadel, S.A.; Tran, D.; Fernandez, E.; Bhatnagar, N.; et al. Populations at risk for severe or complicated influenza illness: Systematic review and meta-analysis. BMJ 2013, 347, f5061. [Google Scholar] [CrossRef] [PubMed]
  4. Van Kerkhove, M.D.; Vandemaele, K.A.H.; Shinde, V.; Jaramillo-Gutierrez, G.; Koukounari, A.; Donnelly, C.A.; Carlino, L.O.; Owen, R.; Paterson, B.; Pelletier, L.; et al. Risk factors for severe outcomes following 2009 influenza A (H1N1) infection: A global pooled analysis. PLoS Med. 2011, 8, e1001053. [Google Scholar] [CrossRef] [PubMed]
  5. Vousden, N.; Bunch, K.; Knight, M.; Group, U.I.C.-I. Incidence, risk factors and impact of seasonal influenza in pregnancy: A national cohort study. PLoS ONE 2021, 16, e0244986. [Google Scholar] [CrossRef]
  6. Mertz, D.; Lo, C.K.; Lytvyn, L.; Ortiz, J.R.; Loeb, M.; Flurisk, I. Pregnancy as a risk factor for severe influenza infection: An individual participant data meta-analysis. BMC Infect. Dis. 2019, 19, 683. [Google Scholar] [CrossRef]
  7. Morgan, O.W.; Bramley, A.; Fowlkes, A.; Freedman, D.S.; Taylor, T.H.; Gargiullo, P.; Belay, B.; Jain, S.; Cox, C.; Kamimoto, L.; et al. Morbid obesity as a risk factor for hospitalization and death due to 2009 pandemic influenza A(H1N1) disease. PLoS ONE 2010, 5, e9694. [Google Scholar] [CrossRef]
  8. Australian Technical Advisory Group on Immunisation (ATAGI). Australian Immunisation Handbook; Australian Government Department of Health and Aged Care: Canberra, Australian, 2022.
  9. Fell, D.B.; Bhutta, Z.A.; Hutcheon, J.A.; Karron, R.A.; Knight, M.; Kramer, M.S.; Monto, A.S.; Swamy, G.K.; Ortiz, J.R.; Savitz, D.A. Report of the WHO technical consultation on the effect of maternal influenza and influenza vaccination on the developing fetus: Montreal, Canada, September 30–October 1, 2015. Vaccine 2017, 35, 2279–2287. [Google Scholar] [CrossRef]
  10. Zaman, K.; Roy, E.; Arifeen, S.E.; Rahman, M.; Raqib, R.; Wilson, E.; Omer, S.B.; Shahid, N.S.; Breiman, R.F.; Steinhoff, M.C. Effectiveness of maternal influenza immunization in mothers and infants. N. Engl. J. Med. 2008, 359, 1555–1564. [Google Scholar] [CrossRef]
  11. Moriarty, L.F.; Omer, S.B. Infants and the seasonal influenza vaccine. A global perspective on safety, effectiveness, and alternate forms of protection. Hum. Vaccines Immunother. 2014, 10, 2721–2728. [Google Scholar] [CrossRef]
  12. Paget, J.; Staadegaard, L.; Wang, X.; Li, Y.; van Pomeren, T.; van Summeren, J.; Dückers, M.; Chaves, S.S.; Johnson, E.K.; Mahé, C.; et al. Global and national influenza-associated hospitalisation rates: Estimates for 40 countries and administrative regions. J. Glob. Health 2023, 13, 04003. [Google Scholar] [PubMed]
  13. Zhao, X.; Gang, X.; He, G.; Li, Z.; Lv, Y.; Han, Q.; Wang, G. Obesity Increases the Severity and Mortality of Influenza and COVID-19: A Systematic Review and Meta-Analysis. Front. Endocrinol. 2020, 11, 595109. [Google Scholar] [CrossRef] [PubMed]
  14. McLarnon, A. Obesity: Influenza immunity impaired in obesity. Nat. Rev. Endocrinol. 2012, 8, 3. [Google Scholar]
  15. Kim, Y.-H.; Kim, J.-K.; Kim, D.-J.; Nam, J.-H.; Shim, S.-M.; Choi, Y.-K.; Lee, C.-H.; Poo, H. Diet-induced obesity dramatically reduces the efficacy of a 2009 pandemic H1N1 vaccine in a mouse model. J. Infect. Dis. 2012, 205, 244–251. [Google Scholar] [PubMed]
  16. Frasca, D.; Ferracci, F.; Diaz, A.; Romero, M.; Lechner, S.; Blomberg, B.B. Obesity Decreases B Cell Responses in Young and Elderly Individuals. Obesity 2016, 24, 615–625. [Google Scholar] [PubMed]
  17. Sheridan, P.A.; Paich, H.A.; Handy, J.; Karlsson, E.A.; Hudgens, M.G.; Sammon, A.B.; Holland, L.A.; Weir, S.; Noah, T.L.; Beck, M.A. Obesity is associated with impaired immune response to influenza vaccination in humans. Int. J. Obes. 2012, 36, 1072–1077. [Google Scholar]
  18. de Heredia, F.P.; Gomez-Martinez, S.; Marcos, A. Obesity, inflammation and the immune system. Proc. Nutr. Soc. 2012, 71, 332–338. [Google Scholar] [CrossRef]
  19. Tagliabue, C.; Principi, N.; Giavoli, C.; Esposito, S. Obesity: Impact of infections and response to vaccines. Eur. J. Clin. Microbiol. Infect. Dis. 2016, 35, 325–331. [Google Scholar]
  20. Clarke, M.; Goodchild, L.M.; Evans, S.; Giles, L.C.; Sullivan, S.G.; Barr, I.G.; Lambert, S.; Marshall, H. Body mass index and vaccine responses following influenza vaccination during pregnancy. Vaccine 2021, 39, 4864–4870. [Google Scholar]
  21. Sperling, R.S.; Engel, S.M.; Wallenstein, S.; Kraus, T.A.; Garrido, J.; Singh, T.; Kellerman, L.; Moran, T.M. Immunogenicity of trivalent inactivated influenza vaccination received during pregnancy or postpartum. Obstet. Gynecol. 2012, 119, 631–639. [Google Scholar]
  22. Australian Institute of Health and Welfare. Overweight and Obesity; Internet; Australian Institute of Health and Welfare: Canberra, Australian, 2024. [Google Scholar]
  23. World Health Organization. Prevalence of Obesity Among Adults, BMI >= 30 (Age-Standardized Estimate) (%). 2024. Available online: https://www.who.int/data/gho/data/indicators/indicator-details/GHO/prevalence-of-obesity-among-adults-bmi-=-30-(age-standardized-estimate)-(-) (accessed on 11 October 2024).
  24. WHO Global Influenza Surveillance Network. Manual for the Laboratory Diagnosis and Virological Surveillance of Influenza. 2011. Available online: https://www.who.int/publications/i/item/manual-for-the-laboratory-diagnosis-and-virological-surveillance-of-influenza (accessed on 8 May 2019).
  25. The European Agency for the Evaluation of Medicinal Products. Note for Guidance on Harmonisation of Requirement for Influenza Vaccines. Committee for Proprietary Medicinal Products, [Internet]. (CPMP/BWP/214/96). 1997. Available online: https://www.ema.europa.eu/en/documents/scientific-guideline/note-guidance-harmonisation-requirements-influenza-vaccines_en.pdf (accessed on 17 September 2021).
  26. de Jong, J.C.; Palache, A.M.; Beyer, W.E.; Rimmelzwaan, G.F.; Boon, A.C.; Osterhaus, A.D. Haemagglutination-inhibiting antibody to influenza virus. Dev. Biol. 2003, 115, 63–73. [Google Scholar]
  27. Hobson, D.; Curry, R.L.; Beare, A.S.; Ward-Gardner, A. The role of serum haemagglutination-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J. Hyg. 1972, 70, 767–777. [Google Scholar]
  28. Coudeville, L.; Bailleux, F.; Riche, B.; Megas, F.; Andre, P.; Ecochard, R. Relationship between haemagglutination-inhibiting antibody titres and clinical protection against influenza: Development and application of a bayesian random-effects model. BMC Med. Res. Methodol. 2010, 10, 18. [Google Scholar]
  29. Neidich, S.; Milner, J.; Patel, N.; Hudgens, M.; Beck, M.; Xiao, P.-J.; Mensah-Biney, K. The effect of BMI on the immunoglobulin subclass response to influenza vaccination. FASEB J. 2014, 28, 382.1. [Google Scholar]
  30. Sweet, M.A.; McCullers, J.A.; Lasala, P.R.; Briggs, F.E.; Smithmyer, A.; Khakoo, R.A. Comparison of immune response to the influenza vaccine in obese and nonobese healthcare workers. Infect. Control Hosp. Epidemiol. 2015, 36, 249–253. [Google Scholar] [PubMed]
  31. Talbot, H.; Coleman, L.; Crimin, K.; Zhu, Y.; Rock, M.; Meece, J.; Shay, D.; Belongia, E.; Griffin, M. Association between obesity and vulnerability and serologic response to influenza vaccination in older adults. Vaccine 2012, 30, 3937–3943. [Google Scholar]
  32. Chauvin, C.; Retnakumar, S.V.; Bayry, J. Obesity negatively impacts maintenance of antibody response to COVID-19 vaccines. Cell Rep. Med. 2023, 4, 101117. [Google Scholar] [PubMed]
  33. van der Klaauw, A.A.; Horner, E.C.; Pereyra-Gerber, P.; Agrawal, U.; Foster, W.S.; Spencer, S.; Vergese, B.; Smith, M.; Henning, E.; Ramsay, I.D.; et al. Accelerated waning of the humoral response to COVID-19 vaccines in obesity. Nat. Med. 2023, 29, 1146–1154. [Google Scholar]
  34. Mohammed, H.; Roberts, C.T.; Grzeskowiak, L.E.; Giles, L.C.; Dekker, G.A.; Marshall, H.S. Safety and protective effects of maternal influenza vaccination on pregnancy and birth outcomes: A prospective cohort study. EClinicalMedicine 2020, 26, 100522. [Google Scholar]
  35. Lakhan, N.; Clarke, M.; Mathew, S.M.; Marshall, H. Retrospective review of factors associated with severe hospitalised community-acquired influenza in a tertiary paediatric hospital in South Australia. Influenza Other Respir. Viruses 2016, 10, 479–485. [Google Scholar]
  36. Caini, S.; Meijer, A.; Nunes, M.C.; Henaff, L.; Zounon, M.; Boudewijns, B.; Del Riccio, M.; Paget, J. Probable extinction of influenza B/Yamagata and its public health implications: A systematic literature review and assessment of global surveillance databases. Lancet Microbe 2024, 5, 100851. [Google Scholar] [PubMed]
  37. World Health Organization. Recommended Composition of Influenza Virus Vaccines for Use in the 2024–2025 Northern Hemisphere Influenza Season. 23 February 2024. Available online: https://www.who.int/publications/m/item/recommended-composition-of-influenza-virus-vaccines-for-use-in-the-2024-2025-northern-hemisphere-influenza-season (accessed on 30 August 2024).
  38. Xu, Q.; Wei, H.; Wen, S.; Chen, J.; Lei, Y.; Cheng, Y.; Huang, W.; Wang, D.; Shu, Y. Factors affecting the immunogenicity of influenza vaccines in human. BMC Infect. Dis. 2023, 23, 211. [Google Scholar]
  39. Wen, S.; Wu, Z.; Zhong, S.; Li, M.; Shu, Y. Factors influencing the immunogenicity of influenza vaccines. Hum. Vaccines Immunother. 2021, 17, 2706–2718. [Google Scholar]
  40. Trombetta, C.M.; Montomoli, E. Influenza immunology evaluation and correlates of protection: A focus on vaccines. Expert. Rev. Vaccines 2016, 15, 967–976. [Google Scholar]
  41. Reber, A.; Katz, J. Immunological assessment of influenza vaccines and immune correlates of protection. Expert. Rev. Vaccines 2013, 12, 519–536. [Google Scholar]
  42. Neidich, S.D.; Green, W.D.; Rebeles, J.; Karlsson, E.A.; Schultz-Cherry, S.; Noah, T.L.; Chakladar, S.; Hudgens, M.G.; Weir, S.S.; Beck, M.A. Increased risk of influenza among vaccinated adults who are obese. Int. J. Obes. 2017, 41, 1324–1330. [Google Scholar]
Vaccines 12 01307 g001
Figure 1. Participant flow chart.
Figure 1. Participant flow chart.
Vaccines 12 01307 g001
Vaccines 12 01307 g002
Figure 2. Pre- and post-vaccination HI titres by BMI category for (a) A/H3N2; (b) A/H1N1; (c) B/Victoria; and (d) B/Yamagata.
Figure 2. Pre- and post-vaccination HI titres by BMI category for (a) A/H3N2; (b) A/H1N1; (c) B/Victoria; and (d) B/Yamagata.
Vaccines 12 01307 g002
Table 1. Participant summary and characteristics.
Table 1. Participant summary and characteristics.
CharacteristicBMI < 30 kg/m2BMI ≥ 30 kg/m2
n = 52n = 21
Maternal age at vaccination
mean years, SD [range]		32.8 (4.6) [24–44]31.7 (4.5) [21–39]
Maternal BMI (first trimester)
mean kg/m2, (SD) [range]		25.7 (2.5) [19.4–29.9]34.3 (4.6) [30.1–43.7]
Country of birth (Australia) (%) yes37/52 (71%)15/21 (71%)
Maternal gestation at vaccination
mean completed weeks, (SD) [range]		23.6 (7.4) [11–37]23.7 (6.8) [13–33]
Prior influenza vaccination (ever) (%) yes39/52 (75%)15/21 (71%)
Pertussis vaccine coadministered (%) yes21/52 (40%)11/21 (52%)
Infant gestation at delivery
mean completed weeks, SD [range]		38.4 (1.8) [31–42]38.6 (1.0) [37–41]
Infant Sex (Male: Female: Unknown)25:24:312:8:1
Interval between vaccination and blood sample:
1 m post-vaccination: Mean days (SD) [range]31 (8.1) [21–56]31 (7.5) [21–47]
6 m post-vaccination: Mean days (SD) [range]180 (13.6) [166–222]184 (16.7) [166–227]
Cord blood: Mean days post-vaccination (SD) [range]106 (51.8) [13–196]105 (53.5) [39–193]
Table 2. Immune responses to influenza vaccine in pregnant women by influenza type/lineage and BMI category at each sample timepoint.
Table 2. Immune responses to influenza vaccine in pregnant women by influenza type/lineage and BMI category at each sample timepoint.
A/H3N2A/H1N1B/VictoriaB/Yamagata
BMI < 30 kg/m2BMI ≥ 30 kg/m2p ValueBMI < 30 kg/m2BMI ≥ 30 kg/m2p ValueBMI < 30 kg/m2BMI ≥ 30 kg/m2p ValueBMI < 30 kg/m2BMI ≥ 30 kg/m2p Value
GMT (95% CI)Pre-vaccination71.0
(48.8–103.1)		67.8
(34.0–135.3)		0.9866.4
(48.2–91.4)		67.8
(38.6–119.2)		0.9349.5
(38.7–63.3)		27.8
(17.9–43.3)		0.03120.9
(89.9–162.7)		72.5
(36.8–142.9)		0.34
1 month post215.3
(157.1–295.0)		242.5
(137.1–429.1)		0.92430.7
(313.6–591.6)		662.6
(360.4–1218.1)		0.31147.0
(112.4–192.2)		117.1
(83.3–164.7)		0.41294.0
(224.1–385.7)		223.8
(125.3–399.6)		0.58
GMTR
(1 m/pre)		3.01
(2.26–4.01)		3.86
(2.06–7.23)		0.566.37
(4.17–9.76)		10.93
(5.09–23.42)		0.193.01
(2.29–3.97)		4.43
(2.76–7.13)		0.192.43
(1.83–3.25)		3.32
(1.47–7.54)		0.58
6 months post188.0
(130.8–270.3)		180.8
(107.1–305.1)		0.85272.4
(198.8–373.3)		376.7
(185.7–764.3)		0.4395.5
(70.6–129.2)		60.1
(39.6–91.4)		0.09224.5
(164.0–307.1)		160.0
(98.2–260.7)		0.66
GMTR
(6 m/1 m)		0.75
(0.63–0.89)		0.59
(0.43–0.79)		0.200.64
(0.53–0.76)		0.57
(0.37–0.86)		0.650.68
(0.57–0.81)		0.54
(0.38–0.77)		0.240.76
(0.65–0.89)		0.76
(0.50–1.16)		0.63
Cord blood242.51
(61.0–365.1)		204.4
(102.6–407.2)		0.61332.9
(232.2–477.4)		640
(340.9–1201.7)		0.12114.3
(76.5–170.7)		70.8
(38.6–129.9)		0.28320
(219.1–467.3)		250.6
(138.9–452.1)		0.67
GMTR
(cord/1 m)		1.00
(0.78–1.28)		0.78
(0.52–1.19)		0.280.92
(0.74–1.18)		0.92
(0.60–1.42)		0.840.77
(0.63–0.94)		0.64
(0.43–0.95)		0.601.04
(0.87–1.25)		1.06
(0.65–1.17)		0.71
% HI ≥ 40Pre-vaccination39/52 (75%)15/21 (71%)0.7539/52 (75%)17/21 (81%)0.5941/52 (79%)10/21 (48%)<0.0148/52 (92%)16/21 (76%)0.06
1 month post47/49 (96%)20/20 (100%)0.3649/49 (100%)20/20 (100%)-49/49 (100%)20/20 (100%)-49/49 (100%)19/20 (95%)0.11
6 months post41/43 (95%)16/17 (94%)0.8442/43 (98%)17/17 (100%)0.5338/43 (88%)14/17 (82%)0.5443/43 (100%)15/17 (88%)0.02
Cord blood33/35 (94%)15/17 (88%)0.4435/35 (100%)17/17 (100%)-32/35 (91%)13/17 (76%)0.1435/35 (100%)16/17 (94%)0.15
Table 3. Univariate and multivariable binomial regression models for association between BMI categories and seroprotection (HI Titre ≥ 40 for all four influenza strains at each sample timepoint).
Table 3. Univariate and multivariable binomial regression models for association between BMI categories and seroprotection (HI Titre ≥ 40 for all four influenza strains at each sample timepoint).
TimepointHI ≥ 40 for All 4 StrainsRR (95% CI)p ValueaRR * (95% CI)p Value
BMI < 30 kg/m2BMI ≥ 30 kg/m2
Pre-vaccination27/52 (52%)7/21 (33%)0.64 (0.33–1.24)0.19
1 month post47/49 (96%)19/20 (95%)0.99 (0.88–1.11)0.870.94 (0.83–1.06)0.30
6 months post36/43 (84%)12/17 (71%)0.84 (0.60–1.18)0.320.75 (0.53–1.08)0.13
Cord blood30/35 (86%)11/17 (65%)0.75 (0.52–1.10)0.140.75 (0.54–1.05)0.10
* Post-vaccination timepoints are adjusted for trimester at vaccination and coadministration of pertussis.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Clarke, M.; Mathew, S.M.; Giles, L.C.; Barr, I.G.; Richmond, P.C.; Marshall, H.S. The Impact of Obesity on Influenza Vaccine Immunogenicity and Antibody Transfer to the Infant During Pregnancy. Vaccines 2024, 12, 1307. https://doi.org/10.3390/vaccines12121307

AMA Style

Clarke M, Mathew SM, Giles LC, Barr IG, Richmond PC, Marshall HS. The Impact of Obesity on Influenza Vaccine Immunogenicity and Antibody Transfer to the Infant During Pregnancy. Vaccines. 2024; 12(12):1307. https://doi.org/10.3390/vaccines12121307

Chicago/Turabian Style

Clarke, Michelle, Suja M. Mathew, Lynne C. Giles, Ian G. Barr, Peter C. Richmond, and Helen S. Marshall. 2024. "The Impact of Obesity on Influenza Vaccine Immunogenicity and Antibody Transfer to the Infant During Pregnancy" Vaccines 12, no. 12: 1307. https://doi.org/10.3390/vaccines12121307

APA Style

Clarke, M., Mathew, S. M., Giles, L. C., Barr, I. G., Richmond, P. C., & Marshall, H. S. (2024). The Impact of Obesity on Influenza Vaccine Immunogenicity and Antibody Transfer to the Infant During Pregnancy. Vaccines, 12(12), 1307. https://doi.org/10.3390/vaccines12121307

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop