Pertussis vaccination – an

update Ute Hallbauer

Department Paediatrics and Child Health University of the Free State

One of the most prevalent vaccine-

preventable diseases

Pertussis

• Diagnosis

• The increasing incidence and the morbidity

• Why is there an increase?

• How should the pertussis problem be tackled?

Difficulty in estimating number of cases and true incidence

• Variable clinical presentation •  Few people seek help •  Clinicians don’t always suspect pertussis

• Heterogenous diagnostic approaches •  Few places have resources for laboratory confirmation •  Clinical and laboratory diagnostic cases often go unreported •  Diverse laboratory tests available

• Different surveillance systems

Case Definition • Clinical case definition (WHO)# :

•  ≥ 2 weeks of cough plus one of: •  Paroxysms, inspiratory whoop, post-tussive vomiting

•  Laboratory confirmed. Any cough duration plus: •  Culture positive or •  PCR positive •  Positive paired serology

NB. Laboratory confirmation is not required for notification in South Africa

# http://www.who.int/immunization_monitoring/diseases/pertussis_surveillance/en/

Improved Diagnostics

•  Improved diagnosis and subsequent reporting • Volume of PCR based testing (correct technique with

experience, contamination may be problem with high volume) •  IS481

•  Used in many assays •  Higher sensitivity, decreases with increasing cough duration •  [Also found in B. holmesii, which does not occur in Africa] •  Less specific

• Still limited testing in low income countries

1957

1994

1940’s whole cell pertussis vaccine

1990’s change to acellular pertussis vaccine

Druzian AF et al. Pertussis in the central-west region of Brazil: one decade study. Braz J Inf Dis 2014;18(2):

177-180

Wymann MN et al. Prospective pertussis surveillance in Switzerland, 1991 – 2006. Vaccine 2011;29:2058-2065

Pertussis is a disease of adolescents and adults……..

Country 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002

Algeria 104 1 0 1 28 0 23 18 7 22 57

Angola 1259 1554 2539 1127 1148 921 1328 0 1675 2654 0

Benin 0 0 53 0 0 0 99 49

Botswana 0 0 0 0 0 0 0 0 0

Burkina Faso 0 6 13 68 171 44 54 170 420 171 212

Burundi 0 0 0 0 0 0 0 0 154

Cameroon Cape Verde 0 1 0 6 0 0 0 7 0

Central African Republic (the) 124 100 1 63 2 65 87 561 80 10

Chad Comoros (the) 0 0 0 0 0 0 0 0

Congo (the) 12 0 0 0 0 55 108 0 38

Côte d'Ivoire 0 0

DR Congo 3407 2452 2157 830 3190 3799 3558 4564 7104 2534

Equatorial Guinea 0 0 0

Eritrea 208 91 11 0 30 65 46 6 53 149

Country 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002

Namibia 2 16 0 0 15 0 8 7 22 10

Niger (the) 0 983 30 1354 1199 3204 1985 1206 2159 2109 2613

Nigeria 11628 0 11281 13240 12573 10997 15609 10976 11894

Rwanda 0 0 0 0 0 0 0

Sao Tome and Principe 0 0 0 0 0 0 0 0 0 0 0

Senegal 0 45 50 7 21 0

Seychelles 0 5 2 0 0 0 0 0 0 0 0

Sierra Leone 23 0 0

South Africa 181 4 8 5

South Sudan Swaziland 0 0 6 0 0 0 1 0 0 0 0

Togo 32 34 53 72 156 27 88 71 177

Uganda 0

United Republic of Tanzania 0 0 0 0 0 0 0 0 0 33 1

Zambia 0 0 0 681 162 34 120 185 180 391 595

Zimbabwe 0 0 0 0 0 0 0 0 9 0 0

Year 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 S. African1 Notification 181 4 8 5

RXH2 10 2 7 2 2 3 3 1 6 7 3

South African surveillance data

NICD 311 cases

Cherry JD et al. Clinical definitions of pertussis: Summary of a Global Pertussive Initiative roundtable meeting, February

2011. CID 2012;54(12):1756-1764

Morbidity •  Hospitalization 5.4%

•  Of all hospitalized -  78% were infants < 1 yr (only 12.5% of whole group) - 61% < 3 months

•  Infants < 1year: 25 - 33.5%

•  With increasing age, decrease % hospitalization

•  Those who required ventilation: 95% < 3month

•  > 90% fatalities in < 3 months old Stein-Zamir C, Shoob H, Abramson N, Zentner G. The

impact of additional pertussis vaccine doses on disease incidence in children and infants. Vaccine 2011; 29:207-211

Wymann MN et al. Prospective pertussis surveillance in Switzerland, 1991 – 2006. Vaccine 2011;29:2058-2065

Pertussis is a disease of adolescents and adults………

………..but infants are worst affected

WHY? Reasons for Resurgence

•  Vaccine-driven evolution of Bordetella pertussis problem •  less natural immunity •  shorter vaccine induced immunity, waning of immunity after

immunization •  acellular pertussis vaccine has somewhat limited ability to induce

immunological memory compared to whole-cell vaccine •  cessation of natural immune boosting •  less exposure to pertussis •  adults as source of infection

WHY? Reasons for Resurgence

• Switch from whole cell to acellular vaccines in 1990’s , imperfect vaccine

•  wP promotes Th1 response, aP a Th2 and Th17 response •  Incomplete protection from vaccination

•  Changing strains: mutations in pertussis toxin and pertactin •  Do we know the serological correlate of immunity?

•  Improved surveillance, increased awareness (literature and press)

• Changes in diagnostic tests

Mills KHG et al. Do we need a new vaccine to control pertussis? Trends in Microbiology 2014;22(2):49

WHY? Reasons for Resurgence

Waning of immunity •  Following both vaccination and infection

•  Duration of protection o  after natural infection: 7-20 years o  whole cell: 4 – 14 years o acellular: 5-6 years

•  Reduced opportunities for boosting immunity

•  Decreased circulation of Bordetella pertussis organism

Cherry J et al. Pediatrics 2003; 115: 1422–1427

Wendelboe A et al Pediatr Infect Dis J 2005; 24: S58–S61

Resurgence was predicted using mathematical model Assumptions

…..We conclude that the alarming resurgence of pertussis among adults and adolescents in Britain and elsewhere may simply be a legacy of historically inadequate coverage employing imperfect vaccines. Indeed, we argue that the absence of resurgence at this late date would be more surprising…… Riolo MA, King AA, Rohai P.

Can vaccine legacy explain the British pertussis resurgence?

Vaccine 2013;31:5903-8

• Lifelong immunity after natural infection (70yrs)

• Gain of susceptible members: after vaccination, newborn, elderly

• Age 75 years • Vaccine 85% efficacy

Declining vaccination coverage •  Important to maintain the

primary vaccination series

•  Unvaccinated patients have higher risk of developing complications

•  With increasing vaccination doses risk of complications and disease severity decreases

Older children and adults as source of infection – a prominent role •  Reservoirs – pre-school children, adolescents and adults

with waning immunity •  Transmission of pertussis unvaccinated/partially

vaccinated infants •  Household contact(s) in up to 83% •  School outbreaks affecting adolescent disease

Elliot E et al. Pediatr Infect Dis J 2004; 23: 246–252

Wendelboe AM et al. Pediatr Infect Dis J , 2005, 24(Suppl. 5):S58-S61

Edwards K. Pediatr Infect Dis J 2005; 24: S104–S108

Van der Maas NAT et al. Pertussis in the Netherlands, is the current vaccination strategy sufficient to reduce disease burden in young infants? Vaccine 2013;31:4541-4547

Pertussis antigens in vaccine

• Pertussis toxin (ptxP, ptxA) • Pertactin (prn) • Fimbrial antigens (fim 2 and fim 3) • Filamentous haemaglutinin (FHA)

Strain changes: Antigenic divergence

• Suggestion that pertussis toxin (PT ) and pertactin (PRN) strains have now changed such that they are distinct from the vaccine strain

•  Godfroid F, et al. Expert Rev Vaccines 2005; 4: 757–778

• Strains produce more PT. PT inhibits innate and adaptive immunity

•  Mooi FR. Bordetella pertussis and vaccination: the persistence of a genetically monomorphic pathogen. Infection, Genetics and Evolution 2010;10(1):36-49

•  Van Gent M et al. SNP-based typing: a useful tool to study Bordetella pertussis populations. PLoS ONE 2011;65(5):e20340. Epub 2011/06/08

•  Mooi FR et al. Bordetella pertussis strains with increased toxin production associated with pertussis resurgence. Emerging Infectious Diseases 2009;15(8):1206-13 Epub 2009/09/16

Van Gent et al. Small mutations in Bordetella pertussis are associated with selective sweeps. PloS ONE 2012

Temporal trends in strain frequencies and notifications in The Netherlands in the period 1949–2010

Vaccination strategies To decrease pertussis in the population • wP vs aP – do we keep what we have? • Combination of wP and aP •  Boosting strategy

To protect the young infants • Cocooning •  Vaccinate neonate (birth, 1 month) – not recommended by WHO •  Vaccinate mother in 3rd trimester pregnancy •  Vaccinate health care workers – cost effective if high coverage •  Vaccinate adults and older people

Adult & adolescent (booster) vaccination

• Reduction in the adult/adolescent reservoir •  Repeat vaccination every 10 years

• Booster dose of Tdap •  Universal vaccination for adolescents

• Cocoon strategy •  Vaccination of household members, including parents and siblings of

newborn infants – not very practical, poor coverage

Stein-Zamir C, Shoob H, Abramson N, Zentner G. The impact of additional pertussis vaccine doses on disease incidence in children and infants. Vaccine 2011; 29:207-211

Despite extra dTap no decrease in rates among infants

Earlier immunization not recommended •  Immunisation at birth • Acellular pertussis vaccine at birth and 1 month induces

significantly higher IgG antibody against pertussis antigens by 2 months of age

• No reduction in pertussis antibody responses – larger and more detailed studies needed

• BUT: • May interfere with antibody response to other vaccines • Lower antibody response at 7 months (one study)

- Halasa N et al. 45th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington DC, USA, 2005

- Wood N et al Pediatr Infect Dis J. 2010 Mar;29(3):209-15

Maternal vaccination during pregnancy

• Placental transfer of pertussis specific antibodies to the fetus • Tdap during pregnancy increases antibody titers to pertussis in

mother • Reduced maternal risk of developing pertussis - > reduced

exposure of infant • Maternal Tdap may prevent neonatal pertussis infection by

presence in infant of passive antibodies • Augmentation of protective pertussis antibodies via antibodies

(mainly IgA) in breast milk: potentiate local immunity in nasopharynx

Raya BA et al. The induction of breastmilk specific antibodies following gestational tetanus-diphtheria-acellular pertussis vaccination. Vaccine

2014;32:5632-5637

Raya BA et al. The effect of timing of maternal tetanus, diphtheria, and acellular pertussis (Tdap) immunization

during pregnancy on newborn pertussis antibody levels – A prospective study. Vaccine 2014;32:5787-5793

Maternal vaccination during pregnancy •  Best 8-12 weeks before delivery: 27 - 36 weeks, but more effective

at 27 - 30 weeks • Highest mean umbilical cord IgG if vaccinate 27-30 wks (< 28 days

before delivery). Higher Ab levels sustained. Half life of IgG 36 days. • No protective level of Ab has been defined. • Maternal Ab’s transferred do not interfere with infant’s response to

subsequent vaccination against pertussis or other Ag’s. • Might protect the prem infant as well •  Encourage doctors and midwives to recommend pertussis

vaccination •  Promote awareness among general (pregnant) public about

pertussis and safety of vaccine in pregnancy

Vaccinating the (paediatric) health carer worker

INFECTED FROM:  Household members  Colleagues  Patients

PROTECT: o  Neonates o  Infants o  High risk patients o  Other HCW’s o  Colleagues o  Own household members

NOSOCOMIAL INFECTION:   Disruptive (off work until 5 days

prophylaxis)   Potential of further spread   Expensive (diagnosis, treatment,

antibiotics) HEALTH CARE WORKER VACCINATION   70 – 92% efficacy   Especially those working with neonates and

infants   Include their own household   Repeat 10 years   Do not need post-exposure antibiotics   Benefit: ethical and economic viewpoint

Heininger U. Vaccination of health care workers against pertussis: Meeting the need for safety within hospitals.

Vaccine 2014;32:4840-4843

Bechini A et al. acellular pertussis vaccine use in risk groups (adolescents, pregnant women, newborns and health care workers): A review of evidences and

recommendations. Vaccine 2012;30:5179-5190

Improved and newer vaccines (might require trials)

• Use of stronger adjuvants → Th1 responses •  Increase dose of antigens in current vaccines • Use genetically or peroxide detoxified toxins • Add other antigens: adenylate cyclase & lipopolysaccharide • Derive newer vaccines from circulating strains (uncertain effect) • Live attenuated B. Pertussis

Pertussis Vaccination at present – the aims

•  To reduce the risk of severe pertussis disease in the infant

•  To achieve good herd immunity 92-95% population must be immune: booster doses

•  Control of disease should be aim, eradication is still far away