Vaccine 25 (2007) 3980–3986

Freezing temperatures in the vaccine cold chain:

A systematic literature review

Dipika M. Matthias a,∗, Joanie Robertson a,1, Michelle M. Garrison b,2,

Sophie Newland a,1, Carib Nelson a,1

a PATH, 1455 NW Leary Way, Seattle, WA 98107, USA b Child Health Institute – University of Washington Box 3564920 Seattle, WA 98195, USA

Received 19 December 2006; received in revised form 7 February 2007; accepted 16 February 2007

Available online 7 March 2007

Abstract

The dangers of accidental freezing of vaccines in the cold chain have prompted studies throughout the globe to better characterize the

risk. To date, there has been no systematic review of these studies. This analysis highlights that accidental freezing is pervasive and occurs

across all segments of the cold chain. Between 14% and 35% of refrigerators or transport shipments were found to have exposed vaccine to

freezing temperatures, while in studies that examined all segments of distribution, between 75% and 100% of the vaccine shipments were

exposed. More rigorous study designs were associated with higher levels of freeze exposure. As more expensive, freeze-sensitive vaccines

are introduced into immunization schedules, freeze prevention will become increasingly critical for ensuring that the world’s children are

receiving fully potent vaccine.

© 2007 Elsevier Ltd. All rights reserved.

Keywords: Freeze-sensitive vaccines; Accidental freezing; Cold chain

1. Introduction

Vaccines are powerful public health tools that save an

estimated 3 million lives each year [1]. Recognizing their

importance, the global health community has prioritized the

increased availability of vaccines to all the world’s children.

Yet this commitment has also had the effect of placing additional stress on an already fragile cold chain, the distribution

network of equipment and procedures used to maintain vaccine quality from the vaccine manufacturer to the vaccine

recipient.

∗ Corresponding author. Tel.: +1 206 285 3500; fax: +1 206 285 6619.

E-mail addresses: dmatthias@path.org (D.M. Matthias),

jrobertson@path.org (J. Robertson), garrison@u.washington.edu

(M.M. Garrison), snewland@path.org (S. Newland), cnelson@path.org

(C. Nelson).

1 Tel.: +1 206 285 3500; fax: +1 206 285 6619.

2 Tel.: +1 206 616 1203; fax: +1 206 616 4623.

World Health Organization (WHO) guidelines and manufacturer product inserts recommend that all vaccines except

oral polio vaccine be kept at 2–8 ◦C during in-country distribution. However, a poorly functioning cold chain may deviate

from this target range and expose vaccines to freezing temperatures. Damage from accidental freezing can result in

potency loss for freeze-sensitive vaccines such as diphtheria, tetanus, pertussis, liquid Haemophilus influenzae type

b (Hib), hepatitis B, and inactivated polio virus [2–6]. However, cold chain practices tend to prioritize protecting vaccine

from heat damage, often at the risk of exposure to freezing

temperatures. As a result, accidental freezing of vaccines is

a largely overlooked problem, yet freeze-sensitive vaccines

represented over 31% of the US$ 439 million UNICEF spent

on all vaccines in 2005 [7].

Increased awareness of this danger has prompted studies

of the cold chain, designed to characterize the risks of vaccine

exposure to freezing temperatures. However, to date there

has been no systematic review or cross-comparison of these

0264-410X/$ – see front matter © 2007 Elsevier Ltd. All rights reserved.

doi:10.1016/j.vaccine.2007.02.052
D.M. Matthias et al. / Vaccine 25 (2007) 3980–3986 3981

studies. This paper attempts to review and analyze the current global data on freezing temperatures within the vaccine

cold chain. The objective is to identify the settings in which

freezing occurs and explore common factors among these

studies and settings. It is our hope that this review will help

raise further awareness of the extent to which vaccines are

being exposed to freezing temperatures worldwide as well as

encourage immunization program managers to design studies

to investigate the state of their own cold chains and institute

programmatic actions to prevent potential freeze exposure.

2. Methods

2.1. Identification of cold chain studies

To capture the broadest range of cold chain studies for

inclusion within our analysis, a search for studies published

between January 1985 and June 2006 was performed using

four major electronic databases: PubMed, Popline, Embase,

and Biosis. The term “vaccine” coupled with one of the following terms was searched in all databases: thermostability,

stability, refrigerator, cold chain, storage, and temperature.

In addition, we searched several public health websites for

unpublished studies, including WHO, TechNet21, Epivac,

and BASICS II. Finally, we solicited unpublished studies

from the immunization community through a posting on the

TechNet21 listserv. A total of more than 1200 articles were

identified; the majority of articles were excluded based on

subject matter inferred by the titles, while 117 warranted

further review against our established inclusion criteria:

• Studies collecting primary data on the temperature conditions within existing cold chain infrastructures (during

either transport or storage), using consistent procedures

across the study.

• Studies using temperature-measuring devices that register

freezing temperatures.

The resulting 35 articles that met the inclusion criteria are

listed in Table 1. Of the 35 articles, 25 were published, while

10 were unpublished. Additionally, 3 of the 35 articles were

from non-English sources.

2.2. Data extraction methods

For each of the studies that met the inclusion criteria, the

following information was compiled: the number of samples

measured (number of refrigerators or shipments), the percentage of samples that registered temperatures that were too

cold, the temperature that was used as the cutoff for defining “too cold” in each study (freeze-exposure threshold), the

period and frequency of temperature measurement, the type

of measuring equipment used, the country in which the study

was conducted, and the year in which the study was published

or reported. From articles in which both transport and storage temperature data were collected, information about each

segment was noted separately. Thus, some studies provided

multiple data points.

2.3. Design of analysis

Transport and storage data were analyzed separately to

accommodate for differences in endpoints across the various

studies and also because the factors that could potentially

influence temperature variations could be expected to differ

between transport and storage situations. The data were also

categorized as developed-country versus developing-country

studies to facilitate comparisons across presumed differences

in cold chain infrastructure [8]. To complement descriptive

statistics, a series of multivariate meta-regression analyses

was pursued to identify factors that might be associated with

the level of exposure to freezing temperatures found in either

transport or storage studies.

2.4. Study limitations

To date, a substantial proportion of the worldwide studies

of freezing temperatures in the cold chain have been conducted in the Asia-Pacific region, with this bias reflected in

the study set (13 out of the 35 studies included in the analysis).

Furthermore, almost half of the developed-country studies

were conducted in Australia (7 out of 16 studies). Therefore,

although the study findings may be indicative, they prevent

full characterization of the study outcomes as representative

of the worldwide problem.

In addition to geographic clustering, publication bias –

the potential for studies with only certain types of results

to be published – could also prevent the study results from

being generalized. For this reason, much effort went into finding unpublished studies and resulted in 28% of the study set

(10 out of 35 articles) coming from unpublished sources.

A large percentage of unpublished sources may also better

reflect the likely universe of studies on this topic, as vaccine

freeze-exposure studies are more often conducted internally

to guide systems improvements. Still, the findings from this

study may not be generalized for all subcategories of analysis. For instance, we were only able to find two transport

studies in developed countries, making it difficult to draw

conclusions about vaccine temperature exposure under that

particular scenario [9,10].

3. Results

3.1. Identified studies

Of the 35 articles selected, 17 articles reported on research

that was conducted in developed countries and 18 in developing countries. Each subset was then further divided into

studies evaluating the temperatures of storage versus transport segments of the cold chain (Table 1). Two articles were

dropped prior to the comparative analysis due to an inabil-
3982 D.M. Matthias et al. / Vaccine 25 (2007) 3980–3986

Table 1

Cold chain studies evaluating vaccine storage or transport temperatures below the recommended range

Authors Year Country Unit of analysis Sample

size

Occurrence of temperatures

below freeze threshold (%)

1 Ford and Gibbs [23] 1990 New Zealand Refrigerator 27 26

2 Lugosi and Battersby [24] 1990 Hungary Transport shipment 166 38

3 Thakker and Woods [25] 1992 Great Britain Refrigerator 8 50

4 Bass [26] 1993 Papua New Guinea Refrigerator 17 6

5 Cheriyan [9] 1993 UK Transport shipment 7 0

6 Miller and Harrisa [27] 1994 Australia Vials 59 48

7 Woodyard et al. [28] 1995 USA Refrigerator 27 26

8 Yuan et al. [29] 1995 Canada Refrigerator 135 6

9 Finnegan and Howell [30] 1996 Ireland Refrigerator 111 7

10 Hanjeet et al.a [31] 1996 Malaysia Vials 234 99

11 Jeremijenko et al. [32] 1996 Australia Refrigerator 50 34

12 Guthridge and Miller [10] 1997 Australia Transport shipment 5 40

13 Kone [33] 1997 Mauritania Refrigerator 108 4

14 Steinglass [34] 1997 Kazakhstan Refrigerator 15 67

15 Wawryk et al. [35] 1997 Australia Refrigerator 40 53

16 Gold et al. [36] 1998 Australia Refrigerator 1 100

17 Reimer and Lewis [37] 1998 Australia Refrigerator 52 23

18 Gold et al. [38] 1999 Australia Refrigerator 32 22

19 Battersby and Feilden [39] 2000 Ukraine Refrigerator 1 100

20 Berhane and Demissie [40] 2000 Ethiopia Refrigerator 60 2

21 Bell et al.b [41] 2001 USA Refrigerator 262 15

22 Lewis et al. [42] 2001 Australia Refrigerator 102 36

23 Munck [43] 2001 Kyrgyzstan Refrigerator 19 0

24 TechNet 21 New Delhi

Consultation Report [44]

2001 Nepal Refrigerator 1 100

25 Gazmararian et al. [45] 2002 USA Refrigerator 641 7

26 Ortega Molina et al. [46] 2002 Spain Refrigerator 43 5

27 PATH [47] 2002 E. European Country Refrigerator 185 25

28 PATH/University of

Melbourne [11] 2003 Southeast Asian Country Refrigerator 11 36

Transport shipment 8 75

29 Edstam et al. [48] 2004 Mongolia Transport shipment 240 15

30 Glele Kaka ̈ı [12] 2004 Benin Refrigerator 16 56

Transport shipment 6 50

31 Nelson et al. [13] 2004 Indonesia Refrigerator 14 29

Transport shipment 16 44

32 PATH, Village Reach [14] 2004

South African

Country

Refrigerator 10 80

Transport shipment 8 75

33 PATH/UNICEF [15] 2005 Bolivia Refrigerator 25 60

Transport shipment 11 100

34 McGuire [49] 2006 Kenya, Liberia, Pakistan Transport shipment 90 60

35 Wirkas et al. [16] 2006 Papua New Guinea Refrigerator 16 31

Transport shipment 12 100

a These studies met our original inclusion criteria; however, the reported data points could not be compared on the same basis as the other studies. In the

case of study #6 and #10, the percent of freeze-exposed vials could not be compared to freeze-exposed refrigerators or transport shipments since some of the

vials may have been stored together, thereby obscuring the independence of the reported data points. Therefore, these studies do not appear in the comparative

analysis.

b Additional data was acquired through e-mail correspondence with the author to resolve questions about the reported data such as what temperatures were

measured during transport versus storage legs of cold chain assessment [13,15] how many unacceptable temperature readings were in the freezing range[32]

or how many refrigerators were included per physician practice [41].

ity to compare the reported data points on the same basis as

the other studies (marked with an asterisk in Table 1). Six

of the remaining 33 articles collected data on both transport and storage segments. These data were divided and

grouped with their respective transport and storage study subsets, resulting in a total of 39 data points for the comparative

analysis.

The majority of transport studies analyzed all transport

segments of the cold chain, from central storage to clinics.

Most of the storage studies examined the lower levels of the
D.M. Matthias et al. / Vaccine 25 (2007) 3980–3986 3983

Table 2

Summary of studies

Cold chain segment Developing countries Developed countries

Transport

Number of studies 9 2

Study sample sizea (mean, standard deviation [S.D.]) 61.9 (86.2) 6 (1.4)

Freeze threshold temperature (◦C) (mean, S.D.) −0.4 (1.0) 0 (0)

Year study conducted (mean, S.D.) 2003 (4.9) 1995 (2.1)

Rigorous monitoringb (duration and frequency) 78% 50%

% shipments found below freeze threshold weighted mean (95% CI) 35.3% (14.8–55.8%) 16.7% (0–44.9%)

Storage

Number of studies 14 14

Study sample sizea (mean, S.D.) 35.6 (51.3) 113.6 (168.3)

Freeze threshold temperature (◦C) (mean, S.D.) 0 (0) 0.4 (1.0)

Year study conducted (mean, S.D.) 2002 (4.1) 1997 (3.8)

Rigorous monitoringb (duration and frequency) 50% 29%

% refrigerators found below freeze threshold, weighted mean (95% CI) 21.9% (10.3–33.6%) 13.5% (6.4–20.7%)

a The units of analysis are shipments for the transport studies and refrigerators for the storage studies.

b Rigorous monitoring was calculated by assigning either a 0 or a 1 to both the duration and frequency of monitoring checks and then multiplying the two

assignments to arrive at a single indication (0 or 1) to label the study as having rigorous monitoring or not. For duration of monitoring, anything more than 1

week was assigned a 1. For frequency of monitoring, any study with continuous monitoring was given a 1; spot checks or one time point only measurements

were given a 0.

cold chain, focusing on clinic refrigerators. The size of the

studies varied, ranging from 1 to over 600 refrigerators or

from 5 to over 200 transport shipments. There were also differences in the definition of the freeze-exposure threshold.

While the majority of studies used 0 ◦C for this threshold,

some considered only temperatures below −3 ◦C, while others deemed anything below 2 ◦C as too cold. In some cases,

the definition also included a time element to determine an

unacceptable level of exposure. Another notable variation in

design across the studies was the frequency and duration of

the temperature monitoring.

3.2. Comparison of studies and outcomes

Key study design parameters (sample size, freezeexposure threshold, year the study was conducted, and level

of monitoring rigor) were compared across four study scenarios (developed versus developing country, transport versus

storage). These figures are summarized in Table 2.

4. Discussion

4.1. Analysis of key findings

• During transport, the occurrence of freezing temperatures

was found to be 16.7% in developed countries compared

to 35.3% in developing countries. This difference was not

significant, potentially indicating that the current transport practice common to all countries – vaccines placed

with frozen ice packs inside of insulated carriers – is placing vaccines at risk, regardless of the resource setting

in which it is conducted. Observations indicate that the

WHO-recommended practice of “conditioning” ice packs

(allowing them to begin melting before placing them in

transport cold boxes) is not routinely followed. Alternatively, the lack of statistical significance could also be

driven by the relatively small number of included studies

for the transport analysis in developed countries.

• During storage, the occurrence of exposure to freezing

temperatures was found to be 13.5% in developed countries versus 21.9% in developing countries. Again, this

difference was not found to be statistically significant,

underscoring the fact that vaccine exposure to freezing

temperatures in the cold chain appears to be a truly global

problem, occurring in resource-rich as well as resourcelimited settings.

• The monitoring rigor of the study was found to be a significant predictor of freezing temperatures, implying that

studies designed to gauge freezing temperatures with more

frequent or continuous monitoring were more likely to

report occurrences of vaccine freezing. Studies in both

developed and developing countries with less rigorous

monitoring reported significantly fewer occurrences of

vaccine exposure to freezing temperature than studies in

developing countries with scheduled or continuous monitoring (55% less [p < 0.001], and 40% less [p = 0.001],

respectively). Another important finding was that among

the studies with more rigorous monitoring, there was no

significant difference between developed- and developingcountry status in the occurrence of vaccines exposed to

freezing temperatures ([p = 0.23]).

• In both the transport and storage analyses, the larger studies had less exposure of vaccines to freezing temperatures.

However, after controlling for monitoring rigor in the storage analysis, it appears that the size of the study makes no

difference in the observed proportions of vaccine exposed

to freezing temperatures ([p = 0.18]). In fact, monitoring

rigor was the only variable that carried significance, implying that study methods matter more than location or study
3984 D.M. Matthias et al. / Vaccine 25 (2007) 3980–3986

size in terms of the proportion of vaccine freeze exposure

found.

• In the six studies that analyzed the exposure of vaccine shipments to freezing temperatures as they traveled

through both shipment and storage segments of the cold

chain from either national or regional stores all the way

to health clinics, the findings were even more striking:

between 75% and 100% of the vaccine shipments were

exposed to freezing temperatures at least once during the

distribution process[11–16]. These comprehensive studies

suggest that the risk of damaging freeze-sensitive vaccines

is present in virtually every stage of the cold chain.

4.2. Guidance for future studies

Although this review cannot reach a conclusion about

the proportion of vaccine that is actually damaged by exposure to freezing temperatures or actually results in moderated

immunogenicity, we do know that potency loss does occur

when freeze-sensitive vaccines undergo the phase change

to a frozen state. Many epidemiological studies have also

pointed to vaccine freezing as a possible contributor to low

immune response in vaccinated individuals and the existing

literature relating freeze exposure to potency loss is compelling enough to suggest some degree of impact on immune

response [2–6,17–19]. More lab-based studies are needed to

augment the literature base in order to gain a more precise

understanding of the degree of potency loss associated with

common field conditions. Detailed cold chain studies that

monitor both time and temperature exposure across the entire

length of the cold chain would provide the richest source of

exposure conditions for such purposes.

It is also important to note that only 35 studies could be

found in the global literature to date, highlighting the lack

of attention to conditions which may be undermining immunization efforts worldwide. The sheer paucity of literature is

a call to action for more rigorous and comprehensive studies

that examine the exposure of vaccines to freezing temperatures through all transport and storage segments of the cold

chain.

4.3. Recommendations

Freeze avoidance will become even more critical in the

future as more expensive freeze-sensitive vaccines such as

DTP-hepatitis B, liquid Hib, pneumococcal, and influenza are

introduced into developing-country immunization programs.

Fortunately, accidental exposure to freezing temperatures can

be prevented. The following is a list of simple and proven

tools available today that could help program managers minimize the potential for freeze damage to their vaccines:

• Investigate vaccine freezing in cold chains. WHO recommends that immunization programs use temperaturemonitoring studies to identify where problems are

occurring so that corrective action can be taken. A WHO

protocol has been developed and successfully applied in

several countries [20,11,13–15].

• Apply innovative cold chain practices. Using cool water

packs instead of frozen ice packs during cold box transport

to avoid the freezing commonly associated with improper

ice-pack conditioning [13], storing the more heat-stable

vaccines in air-conditioned rooms, and conducting limited

transport at ambient temperatures are possible freezeprevention approaches.

• Improve training. Recommended changes in training

include educating vaccine managers and handlers about

freeze-sensitive vaccines, providing clear guidelines on

vaccine handling procedures, and increasing the focus on

freeze prevention during supervision.

• Update cold chain infrastructure. Improved cold chain

equipment is an important aspect of freeze prevention.

New refrigerators are being developed that automatically control temperatures and eliminate the possibility

of inadvertent vaccine freezing. At a minimum, min/max

thermometers can help users better understand the range

of temperatures that vaccines are exposed to over time and

can prompt mitigation strategies. Electronic temperaturemonitoring devices are also available to accompany

vaccines during transport and storage, including low-cost

devices that signal exposure to an established freezeexposure temperature [21].

• Take advantage of vaccines’ heat stability. Freezing temperatures damage freeze-sensitive vaccines more quickly

than ambient temperatures. Vaccine vial monitors, heatexposure indicators required on all vaccines distributed by

UNICEF, allow vaccine programs to utilize the natural heat

stability of some vaccines to expose them to temperatures

warmer than 8 ◦C for limited time without risk of heat damage. It may also be possible to allow a slight warming of the

recommended cold chain temperatures to reduce freezing

without causing heat damage [22].

• Create system-wide policy to avoid freeze damage. Policy changes (at the global and country level) are needed

to prioritize the prevention of freezing in the cold chain

and apply resources to raising awareness, training, and

equipment infrastructure.

5. Conclusion

This analysis highlights that exposure of vaccines to freezing temperatures is pervasive, occurring in both developedand developing-country settings, as well as within both the

storage and transport segments of the cold chain. Across the

four scenarios analyzed, the average proportion of exposure

ranges from 14% to 35%. In the six studies that measured

temperatures longitudinally through multiple sections of the

cold chain, between 75% and 100% of the vaccine shipments

were exposed to freezing temperatures. As vaccine availability expands and more expensive, freeze-sensitive vaccines

are introduced into immunization programs, freeze preven-
D.M. Matthias et al. / Vaccine 25 (2007) 3980–3986 3985

tion will become even more essential, both for making the

most productive use of immunization dollars and for ensuring that the world’s children are receiving fully potent and

effective vaccines.

Acknowledgements

These materials were developed at PATH with support from the Bill & Melinda Gates Foundation and

the Bureau for Global Health, United States Agency for

International Development (USAID), under the HealthTech

Program, Cooperative Agreement #GPH-A-00-01-00005-

00. The opinions expressed herein are those of the authors

and do not necessarily reflect the views of either the Bill &

Melinda Gates Foundation or USAID.

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