1 WHO/PI_flu_DRAFT/28 Dec 2015 2

ENGLISH ONLY 3

4

5

PROPOSED ADDENDUM TO: WHO TRS 927, Annex 3. 6

Recommendations for the production and control of influenza vaccine (inactivated) 7

8

LABELLING INFORMATION OF INACTIVATED INFLUENZA VACCINES FOR USE 9

IN PREGNANT WOMEN 10

11

NOTE: 12

This document has been prepared for the purpose of inviting comments and suggestions on the 13 proposals contained therein, which will then be considered by the Expert Committee on 14

Biological Standardization (ECBS). Publication of this early draft is to provide information 15 about the proposed WHO document on Labelling Information of Inactivated Influenza Vaccines 16 for Use in Pregnant Women to a broad audience and to improve transparency of the consultation 17

process. 18

19 The text in its present form does not necessarily represent an agreed formulation of the Expert 20 Committee. Written comments proposing modifications to this text MUST be received by 19 21

February 2016 in the Comment Form available separately and should be addressed to the World 22 Health Organization, 1211 Geneva 27, Switzerland, attention: Department of Essential 23

Medicines and Health Products (EMP). Comments may also be submitted electronically to the 24 Responsible Officer: Dr Hye-Na Kang at email: kangh@who.int. 25 26

The outcome of the deliberations of the Expert Committee will be published in the WHO 27 Technical Report Series. The final agreed formulation of the document will be edited to be in 28 conformity with the "WHO style guide" (WHO/IMD/PUB/04.1). 29

30

© World Health Organization 2015 31

All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health 32 Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: 33 bookorders@who.int). Requests for permission to reproduce or translate WHO publications – whether for sale or for 34 non-commercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-35 mail: permissions@who.int). 36

The designations employed and the presentation of the material in this publication do not imply the expression of any 37 opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, 38 city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps 39 represent approximate border lines for which there may not yet be full agreement. 40 41

WHO/PI flu_DRAFT/28 Dec 2015

Page 2 The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 1 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. 2 Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 3 4 All reasonable precautions have been taken by the World Health Organization to verify the information contained in 5 this publication. However, the published material is being distributed without warranty of any kind, either expressed or 6 implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the 7 World Health Organization be liable for damages arising from its use. 8

9 The named authors [or editors as appropriate] alone are responsible for the views expressed in this publication. 10

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WHO/PI flu_DRAFT/28 Dec 2015

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Contents 1

2

1. Introduction ............................................................................................................... 4 3

2. Background ............................................................................................................... 4 4

3. Scope ......................................................................................................................... 6 5

4. Terminology ............................................................................................................... 6 6

5. Labelling information ................................................................................................ 6 7

6. Conclusions and interpretation of labelling information ..................................... 10 8

Authors and acknowledgements ............................................................................... 10 9

References ................................................................................................................... 10 10

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1. Introduction 1

Morbidity and mortality due to seasonal influenza virus infection is considered as substantial 2

worldwide (1, 2). Pregnant women are especially vulnerable. They have an increased risk of 3

severe disease and death from influenza and the infection may also lead to foetal complications 4

such as stillbirth, neonatal death, preterm delivery and decreased birth weight (3). For these 5

reasons, in 2012, the WHO position paper on vaccines against influenza (3), endorsed by the 6

WHO Strategic Advisory Group of Experts in Immunization (SAGE), recommended the 7

immunization of pregnant women with trivalent inactivated influenza vaccine (IIV) at any stage 8

of pregnancy (3). It also recommended that pregnant women should have the highest priority for 9

countries considering the initiation or expansion of immunization programmes for seasonal 10

influenza vaccination (3). The recommendation is based on evidence of a substantial risk of 11

severe disease in this group and evidence that seasonal influenza vaccine is safe throughout 12

pregnancy and effective in preventing influenza in the women as well as in their young infants, 13

in whom the disease burden is also high (3, 4). However, for various reasons, the 14

implementation of influenza immunization remains suboptimal (5). One reason is the perceived 15

risk of administering influenza vaccine, or indeed any vaccine, to this population group and, in 16

particular, the precautionary language used in some product labels and its likelihood of 17

misinterpretation. 18

This addendum considers the regulatory aspects of product labelling information and provides 19

clarification and interpretation of the labelling information provided in the product insert of IIVs 20

so as to facilitate the much needed immunization of pregnant women. 21

22

2. Background 23

Activities to enhance the uptake of vaccines during pregnancy are important elements of WHO’s 24

ongoing initiative to improve maternal and child health. As part of this work, WHO held a 25

consultation in July 2014 on influenza vaccines for pregnant and lactating women which focused 26

on the clinical data requirements for product labelling information (6). This was organized by the 27

WHO Technology, Norms and Standards Team and the WHO Initiative for Vaccine Research 28

Team and brought together researchers, manufacturers and regulators with experience in 29

vaccines. A further consultation was organized by the WHO Technology, Norms and Standards 30

team in 2015 to review existing guiding principles related to product package information for 31

IIVs as well as to explore the possibility of providing WHO guidance document to help clarify 32

the benefits of vaccination during pregnancy that could remove any negative perceptions and 33

improve uptake of inactivate influenza vaccines during pregnancy (7). Regulatory policy and 34

practice with regard to permitted text in the product insert sections related to pregnancy and 35

lactation from Brazil, Canada, European Union, Ghana, India, Indonesia, Thailand and the 36

United States of America were described. The results of a 2014 survey of the WHO Developing 37

WHO/PI flu_DRAFT/28 Dec 2015

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Country Vaccines Regulators Network regarding the regulatory policies and perceptions of the 1

wording of the product insert related to vaccines use during pregnancy were also presented. The 2

diversity of approach and understanding in different countries and regions was evident. In 3

addition, it became clear that in countries that import IIVs, the format, data and language 4

included in the product insert usually reflected the text approved by the national regulatory 5

authority (NRA) in the respective country of manufacture and licensing. However, some 6

developing countries require additional language that makes the perceived cautionary message 7

for use even stronger. The regulatory position is based on the fact that licensing is product 8

specific and reliant on data generated during the clinical evaluation of the vaccine and submitted 9

by the manufacturer. Pregnant women are usually excluded from clinical studies during vaccine 10

development, so licensure dossiers generally do not include information on safety and efficacy of 11

the particular vaccine in pregnant women. 12

The regulatory language used in the “Specific Populations” section of product labelling reviewed 13

did not contraindicate the use of IIV in pregnant women, nor was it intended to be a barrier to 14

use. Nevertheless, this language may be perceived as opposing advisory statements from 15

National Immunization Advisory Groups (NITAGs) and the WHO SAGE. After careful analysis 16

of data worldwide, the WHO Global Advisory Committee on Vaccine Safety (GACVS) 17

concluded that there was no evidence of adverse pregnancy outcomes associated with 18

vaccination of pregnant women with several inactivated viral or bacterial vaccines, including 19

IIVs (4). This outcome, combined with the known possible serious outcomes of influenza 20

infection in pregnant women, led to the strong advice from the WHO SAGE that the benefits of 21

immunization with IIV outweigh any risk and to the recommendation that immunization of 22

pregnant women should be given the highest priority (4, 8). 23

Regulatory authorities are conscious of the perceived conflict between regulatory and 24

programmatic needs and revision of current practice and language is underway in some countries 25

(9). Others have considered how to integrate post-market surveillance data into the regulatory 26

process (5). Some NRAs include a statement to the effect that their national advisory committee 27

on immunization considers influenza vaccination safe during pregnancy and indicating that the 28

vaccine should be used when needed (10-12). 29

This document arises from the recommendations of the WHO SAGE regarding the advice to 30

immunize pregnant women with IIV and the resulting discussions of the two WHO consultations 31

mentioned above (6,7), as well as discussions at the 2015 meeting of the WHO Expert 32

Committee on Biological Standardization (ECBS Report 2015 to be published later). The 33

intention is to provide clarification and interpretation of the labelling information provided in the 34

product insert of IIVs, as well as to raise awareness of the convergence of the different 35

regulatory positions, in spite of differing approaches, regarding the use of these vaccines in 36

pregnant women. 37

WHO/PI flu_DRAFT/28 Dec 2015

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1

3. Scope 2

This document applies to inactivated influenza vaccines. It is intended for manufacturers, NRAs, 3

end-user programme managers and NITAGS. 4

Although the focus is on IIVs, some of the concepts and guidance given could be expanded to 5

cover other influenza vaccines when sufficient data are available, as well as other inactivated 6

vaccines, such as Td (13) and pertussis vaccines. 7

This document will align with further guidance on the clinical design and evaluation of vaccines 8

in pregnant women in the WHO Guidelines on Clinical Evaluation of Vaccines: Regulatory 9

Expectations that is currently being updated to include expanded text on clinical trials in 10

pregnant women (14,15). 11

Liability issues are beyond the scope of this document. 12

13

4. Terminology 14

The definitions given below apply to the terms as used in this document. They may have 15

different meanings in other contexts. 16

Maternal immunization: Frequently used to refer to vaccination prior to, during, or after 17

pregnancy. For the purposes of this document, “maternal immunization” refers to vaccination 18

during pregnancy. 19

Label(ling): all forms of product information, i.e. label(ling), product/package insert, package 20

leaflet, and prescribing information. 21

22

5. Labelling Information 23

IIVs, like all prescription drugs and biological products, must be accompanied by labelling that 24

summarizes scientific information concerning the safe and effective use of the product. 25

Labelling includes the package insert which is also referred to as prescribing information or 26

summary of product characteristics (SmPC) (16). This component of labelling is the primary 27

mechanism through which regulatory agencies and vaccine manufacturers communicate essential, 28

science-based information that is used by health care professionals in making prescribing 29

decisions and in counseling patients about a product’s risks and benefits. The content and format 30

requirements for labelling are prescribed by regulations specific to the country where the vaccine 31

is licensed and may differ between countries (9,16). Nevertheless, common principles include 32

WHO/PI flu_DRAFT/28 Dec 2015

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that prescribing information must not be misleading and should not contain implied claims or 1

uses for which there is inadequate evidence of safety or effectiveness (17). 2

3

5.1 Indications and Usage 4

The “Indications and Usage” section of labelling communicates a product’s approved 5

indication(s) and should clearly convey the use(s) for which the product has been shown safe and 6

effective. Specific regulatory requirements and standards for demonstrating safety and 7

effectiveness of vaccines may vary between NRAs. However, in general, the standards for 8

demonstrating the safety of a vaccine for its intended indication take into consideration the 9

condition of the recipients and the characteristics of the product. It is expected that data 10

demonstrating the effectiveness of a vaccine for the intended indication and use are derived from 11

adequate and well-controlled clinical studies. While data from related vaccines may be 12

supportive, typically safety and effectiveness are evaluated for the specific vaccine intended for 13

licensure. For currently licensed IIVs, data from adequate and well-controlled studies to evaluate 14

the safety and effectiveness of these vaccines in the pregnant woman or newborn infant may not 15

be available for labelling. Data from studies published in the literature about use of IIV in 16

pregnancy may not have been submitted to NRAs or may not meet the regulatory requirements 17

for evidence of safety and effectiveness. For example, product (brand) specific safety and 18

effectiveness data may not be available. Consequently, the prescribing information for IIVs often 19

does not include an indication and usage statement that specifically addresses use in pregnancy. 20

However, IIVs are not contraindicated for use in pregnancy, and this use is acceptable following 21

a risk-benefit assessment, that may be conducted by the NITAG. In this case, IIVs may be used 22

to immunize pregnant women. 23

24

5.2 Warnings and Precautions 25

The “Warnings and Precautions” section of labelling is intended to describe and identify adverse 26

events that are serious or clinically significant because they have implications for prescribing 27

decisions or for management of patients. To include an adverse event in this section, there should 28

be reasonable evidence of a causal association between the drug and the adverse event but a 29

causal relationship does not have to be established. Serious adverse events may be defined as 30

those that result in the following outcomes: death, is life-threatening, requires in-patient 31

hospitalization or prolongation of existing hospitalization, results in persistent or significant 32

disability/incapacity, or is a congenital anomaly/birth defect. Any medical event that requires 33

intervention to prevent one of the outcomes above may also be considered as serious (18). Other 34

adverse events that do not meet the definition of a serious adverse event, but are clinically 35

WHO/PI flu_DRAFT/28 Dec 2015

Page 8

significant because of implications for prescribing decisions and patient management should also 1

be included under this section. The description of an adverse event in the “Warning and 2

Precaution section” may cross-reference a more detailed discussion of the risk elsewhere in 3

labelling, e.g. “Use in Specific Populations”. 4

A drug or biological product should be contraindicated only in those situations where the risk 5

from use clearly outweighs any possible benefit. Only known hazards, not theoretical 6

possibilities, should be the basis for a contraindication. For example, evidence in humans or 7

animals that the vaccine poses a serious risk of developmental toxicity during pregnancy would 8

usually warrant a contraindication for use during pregnancy. 9

10

5.3 Use in Specific Populations 11

The “Use in Specific Populations” section of labelling summarizes important differences in 12

response or recommendations for use of the product in specific populations. Information relevant 13

to use of a product during pregnancy is generally found under this section and is sometimes 14

referred to as the “Pregnancy subsection” of product labelling. However, depending on the 15

labelling requirements of the NRA where the vaccine was licensed, information regarding use of 16

IIV in pregnancy may also be found in other sections of product labelling, e.g. the “Warnings 17

and Precautions” section (7). The pregnancy subsection of labelling includes data, when 18

available, from reproductive toxicity studies conducted in animal models to assess the potential 19

developmental and reproductive risk of the product. Data that may be available concerning the 20

safety of the product in pregnant women, e.g. data from a pregnancy registry or data derived 21

from clinical trials where pregnant women were inadvertently exposed to the product are also 22

described in this section. As with other sections of the product labeling, country specific 23

requirements prescribe the information and, frequently, the specific wording to be included in the 24

pregnancy subsection about what is known about the risks of use of the product in pregnancy. 25

WHO pre-qualified IIVs generally have prescribing information reflecting the requirements of 26

the regulatory agency in the country of vaccine licensure. Statements included in the pregnancy 27

subsection of labeling often have been precautionary, e.g. “should be used only following advice 28

of a health care professional”, “if pregnant, please inform your doctor or pharmacist”, “use 29

only if clearly needed”. Some countries, in an effort to improve the clarity of information 30

included in the pregnancy subsection of the labeling, have recently revised their labelling 31

regulations (9).The revised regulations require that labelling include relevant available clinical 32

information from use of the product in pregnant and lactating women, as well as relevant 33

available animal and pharmacologic data to help inform prescribing decisions and counselling of 34

women about the use of the product during pregnancy and lactation. In general, data from use of 35

vaccines during pregnancy that is included in the pregnancy subsection is derived from post-36

marketing studies and/or from maternal immunization studies published in the literature. 37

WHO/PI flu_DRAFT/28 Dec 2015

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1

Of note, labelling policies for IIVs differ with regard to the information that can be included in 2

the pregnancy subsection of labeling. For example, in the US, according to recent rule making, 3

human data that may be included in the pregnancy subsection for any drug or biological product 4

describe what is known about the risks of use of the product in pregnancy (9,19). These data may 5

be derived from clinical trials, pregnancy exposure registries, other large scale epidemiologic 6

studies, or case series reporting a rare event. However, inclusion of data that imply efficacy for a 7

claim that is not an approved indication cannot be described in this section. In contrast, the 8

European Medicines Agency (EMA) has implemented a policy based on an evaluation of the 9

available published evidence relating to both the safety and effectiveness of IIVs and expects all 10

IIV license holders in the EU to amend the pregnancy subsection of the labelling to include 11

advice that inactivated influenza vaccine can be used during all stages of pregnancy (6). The 12

differences in the manufacturing technologies and residual materials in the final product could be 13

an obstacle in other countries to making recommendations that include several products, as there 14

is the potential for these differences to influence the safety or efficacy of the different vaccines 15

when used in pregnant women (7). 16

17

Data and information contained in the pregnancy subsection of labeling must be approved by the 18

NRA in the country of vaccine licensure; however, use of IIVs in pregnant women is also guided 19

by recommendations from health policy makers (e.g. WHO, ACIP, and other NITAGs). 20

21

6. Conclusions and interpretation of labelling information 22

The general conclusion is that the benefit of vaccination with IIVs among pregnant women 23

usually outweighs the risk for potential adverse effects in the mother or developing foetus when 24

the risk for disease exposure is high, when infection poses a special risk to mother and foetus, 25

and when the vaccine is unlikely to cause harm. In some countries, these recommendations may 26

be included in the pregnancy subsection of labelling. Also, the lack of a specific “indication and 27

usage” statement about use of an IIV in pregnant women does not preclude its use during 28

pregnancy. In particular, licensed IIVs are not contraindicated for use during pregnancy. Thus, 29

programmatic recommendations for use of IIVs during pregnancy are not inconsistent with the 30

labelling. 31

32

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Authors and acknowledgements 1

The first draft of this guidance document was prepared by Dr E. Griffiths, Consultant, United 2

Kingdom; Dr M. Gruber, US FDA, USA; Dr H-N. Kang, World Health Organization, 3

Switzerland; Dr M. Pfleiderer, Paul-Ehrlich-Institut (PEI); and Dr J. Southern, Consultant, South 4

Africa, taking into consideration comments received from the WHO working group meeting on 5

the development of guidelines on labelling information of influenza vaccines intended to be used 6

for pregnant women held in Geneva, Switzerland, 24-25 September 2015, and attended by: 7

Dr D. Baswal, Ministry of Health and Family Welfare, India; Dr G. Coleman, Health Canada, 8

Canada; Dr E. Griffiths. Consultant, UK; Dr M. Gruber, Food & Drug Administration (FDA), USA; 9

Mrs N. Hidayati, The National Agency of Drug and Food Control (NADFC), Indonesia; Mrs T. 10

Jivapaisarnpong, Ministry of Public Health, Thailand; Dr H-N. Kang, World Health 11

Organization, Switzerland; Mr A. Kukrety, CDSCO, India; Dr P. Lambach, World Health 12

Organization, Switzerland; Dr O. C. Lapujade, World Health Organization, Switzerland; Dr A. 13

Meek, World Health Organization, Switzerland; Dr P. Neels, Consultant, Belgium; Dr E. 14

Nkansah, Food and Drugs Authority, Ghana; Dr J. Ortiz, World Health Organization, 15

Switzerland; Dr C. Rodriguez Hernandez, World Health Organization, Switzerland; Dr J. 16

Southern, Consultant, South Africa; Dr M. F. Thees, National Health Surveillance 17

Agency(ANVISA), Brazil; Dr B. Voordouw, Medicines Evaluation Board (MEB), Netherlands. 18

19

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