Overview

Pneumococcal polysaccharide vaccine (23-valent) or PPV 23 contains purified capsular polysaccharides of the 23 most prevalent or invasive pneumococcal types of Streptococcus pneumonia. Through T-cell-independent mechanisms, this vaccine induces antibody production and creates immunity.¹ In Malaysia, PPV 23 is indicated for children from two (2) years of age, adolescents, and adults in whom there is an increased risk of pneumococcal disease.^2-3 There is currently one (1) PPV 23 product registered with the Drug Control Authority (DCA).²

Extensive limb swelling (ELS) is defined as limb swelling (with or without redness) that extends at least to the joints immediately above and below the injection site or that may cross one or more joints.^4-5 Alternatively, ELS can be defined as swelling of the limb that results in twice the normal size of the limb circumference.⁴

Background of the Safety Issue

In September 2022, the National Pharmaceutical Regulatory Agency (NPRA) had learned from the European Medicines Agency (EMA) about the risk of extensive swelling of vaccinated limb with PPV 23. After considering the evidence from post-marketing reports and the literature, the EMA has requested that the package insert for all PPV 23 products be updated with the risk of extensive swelling of vaccinated limb.⁶

Extensive swelling of vaccinated limb is a known adverse event to some other vaccines, such as Comirnaty (COVID-19 mRNA vaccine) and diphtheria/tetanus toxoids/acellular pertussis vaccine (adsorbed paediatric) (DTaP), while the reporting rate differs substantially among vaccines.^7-8 Although the exact mechanism of action is uncertain, it has been suggested that humoral immune responses might be the plausible mechanism for extensive swelling of vaccinated limb. Other possible susceptibility factors include prior sensitisation to antigens or excipients and injection techniques.⁷

Extensive swelling of vaccinated limb usually appears within 24 hours after PPV 23 vaccination and may be associated with other signs of inflammation, such as erythema, warmth, or pain.^7-8 It is possible that these events may be overlooked due to the regular occurrence of injection site inflammation following immunisation. Besides, extensive swelling of vaccinated limb might be misdiagnosed as cellulitis or erysipelas in the lack of bacteriological information, which could result in unnecessary antibiotic treatment.⁸ In general, the symptoms of extensive limb swelling resolve spontaneously without permanent sequelae, with the reported duration ranging around 3–14 days.^7-8

Adverse Events Following Immunisation (AEFI) Reports

The NPRA has received 65 reports with 186 adverse events suspected to be related to PPV 23 products. The most frequently reported adverse events were injection site pain (31), followed by injection site swelling (16) and injection site erythema (9). However, so far, NPRA has not received any local reports of extensive swelling of vaccinated limb.⁹ Globally, out of 78,317 post-marketing reports involving PPV 23, there were 1,119 reports of extensive swelling of vaccinated limb.¹⁰ Assessment of local reports of injection site swelling and erythema could not determine whether the events actually constituted extensive swelling of vaccinated limb, as the size or extent of the swelling was often not recorded on the AEFI reporting form received.⁹ 

Advice for Healthcare Professionals

• Be aware and inform vaccine recipients about the possible occurrence of extensive swelling of vaccinated limb within a short period after administration of PPV 23.
• Reassure vaccine recipients that extensive swelling of vaccinated limb usually recovers spontaneously within a few days without any remaining symptoms. Conventional approaches, such as cooling the limbs, can be used to reduce swelling.
• Remind vaccine recipients to see healthcare professionals if the symptoms worsen or do not improve after a few days.
• Report all suspected adverse events following immunisation with PPV 23 to the NPRA. If unusual swelling occurs, specify the size or extent of the swelling on the AEFI reporting form.

References:

1. National Pharmaceutical Regulatory Agency. Malaysian Product Registration Database (Quest 3+). Pneumovax 23 Vaccine local package insert [Internet]. Revision date: Apr 2022 [cited 2022 Nov 22]. Available from: https://wwww.npra.gov.my
2. National Pharmaceutical Regulatory Agency (NPRA). QUEST 3+ Product Search [Internet]. 2022 [cited 2022 Nov 22]. Available from: https://www.npra.gov.my
3. Malaysian Society of Infectious Diseases and Chemotherapy (MSIDC). Guidelines for Adult Immunisation [Internet]. 3rd ed. 2020 [cited 2022 Nov 22]. Available from: https://adultimmunisation.msidc.my/read-book/   
4. Australian Government Department of Health. Australian Immunisation Handbook. Glossary of technical terms [Internet]. Last update: 22 February 2021 [cited 2022 Nov 22]. Available from: https://immunisationhandbook.health.gov.au/technical-terms
5. Government of Canada. Contraindications and precautions: Canadian Immunization Guide [Internet]. 2022 Sep 16 [cited 2022 Nov 22]. Available from: https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-2-vaccine-safety/page-3-contraindications-precautions-concerns.html
6. European Medicines Agency (EMA). PRAC recommendations on signals: Adopted at the 29 August – 1 September 2022 PRAC meeting [Internet]. 2021 Sep 26 [cited 2022 Nov 22]. Available from: https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-29-august-1-september-2022-prac-meeting_en.pdf
7. Woo EJ, Burwen DR, Gatumu SN, Ball R; Vaccine Adverse Event Reporting System Working Group. Extensive limb swelling after immunization: reports to the Vaccine Adverse Event Reporting System. Clin Infect Dis. 2003 Aug 1;37(3):351-8. Available from: https://doi.org/10.1086/375820
8. The Netherlands Pharmacovigilance Center Lareb. Extensive limb swelling (ELS) after administration of Pneumovax 23. 8 September 2021 [cited 2022 Nov 22]. Available from: https://www.lareb.nl/media/uh3fheik/signals_2021_pneumovax-23-and-extensive-swelling-of-vaccinated-limb.pdf
9. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2022 [cited 2022 Nov 22]. Available from: https://www.npra.gov.my (access restricted)
10. Uppsala Monitoring Centre (UMC). The WHO Global ICSR Database (VigiLyze) [Internet]. 2022 [cited 2022 Oct 25]. Available from: https://www.vigilyze.who-umc.org (access restricted)

DISCLAIMER

This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

Written by: Wang Khee Ing
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Dr. Azuana Ramli