Why are some vaccines more uncomfortable than others?

The Short Version: It is normal to feel crummy shortly after getting a vaccine. Vaccines provoke immune responses, which are uncomfortable and can trigger a number of behavioral changes in us e.g. we want to sleep more, we tend to become socially withdrawn, and we tend to become tired and eat less. There’s a lot that can be done to manage the discomfort after a vaccination, but you should avoid taking anti-inflammatory medications (e.g. acetaminophen and NSAIDs) before and during vaccination (but they are fine to take after).

Reactogenicity: The Concept

If you’re paying attention to the news or watching ACIP and VRBPAC meetings about vaccines, you may be seeing the term “reactogenicity” get used a lot. Reactogenicity is the tendency of a vaccine to cause predictable, but uncomfortable side effects relating to the immune response- things like fever; headache; muscle and joint aches; tiredness; rash; pain, swelling, and redness at the injection site, etc. Needless to say, it is the hope that vaccines will have minimal reactogenicity but excellent protection against disease and strong indirect vaccine effects. Unfortunately, it seems that the more effective a vaccine is, the more likely it is to be reactogenic.

***** Note however that saying a vaccine is reactogenic is NOT the same as saying it is unsafe. Reactogenic effects of a vaccine, while uncomfortable, are self-limiting and do not cause significant harm to a vaccinee’s health (even if they do disrupt daily life for a time). Vaccine safety is much more a question of the possibility of the vaccine to cause adverse reactions, in particular serious adverse reactions such as those that may require advanced medical management e.g. hospitalization, cause disability, or result in death, rather than the self-limiting consequences of a normal immune response.

Irwin MR. 2019. Sleep and inflammation: partners in sickness and in health. Nat Rev Immunol. 19(11):702–715. Figure 1: Sleep and the immune response have a complex relationship; in general the inflammatory mediators produced by immune response enhance slow-wave sleep (SWS), the deepest phase of sleep, and reduce REM (rapid eye movement) sleep (when we dream), which results in more efficient sleep and increased sleep time. This is shown to enhance antiviral responses and promote the survival of the host in the context of infection.

We don’t fully understand in detail why certain vaccines are more reactogenic than others, though we do know some basic principles. Live-attenuated vaccines tend to be more reactogenic than vaccines containing just purified antigens, seemingly because they stimulate the immune system more strongly. Additionally, adjuvants (substances added to the vaccine to enhance the immune response; the most commonly used ones are aluminum salts) can increase the reactogenicity of a vaccine; Shingrix is known to be a very reactogenic vaccine for example, and it contains AS01B, an adjuvant system comprising a liposomal suspension of QS-21 (a saponin), and monophosphoryl lipid A. The Pfizer/BioNTech vaccine appears to be similar in its reactogenicity to Shingrix, though possibly slightly greater based on the pre-licensure data.

Another factor is how the vaccine is administered. Professor Petousis-Harris’s paper on the subject notes that generally intramuscular injection is less reactogenic than subcutaneous injection (in general, adjuvanted vaccines should be given intramuscularly regardless; live attenuated vaccines should be given subcutaneously). Additionally, longer needles were associated with lower reactogenicity, and doing the injection more slowly was also shown to result in lower reactogenicity.

It’s not too difficult to understand why in general an effective vaccine would be reactogenic. Effective vaccines have to stimulate robust immune responses from vaccine recipients, and immune responses are uncomfortable. Most vaccines are given by injection and they have to induce local inflammation. This recruits the machinery of the immune system but results in the 4 key signs of inflammation: heat, pain, swelling, and redness. These mainly occur because blood vessels near the injection site are dilating (causing redness and heat) to let the cells of the immune system in, which causes fluid to leak out (causing swelling), and the factors released by the immune system can be noxious (causing pain). Some pain might also be from the fact that you did just get an injection, which is a needle and it can hurt. The cells of the immune system also make pro-inflammatory cytokines (small proteins that the cells of the immune system use to communicate with each other which promote inflammation) which signal to the liver to make acute-phase proteins that enhance the immune response. But the pro-inflammatory cytokines can also provoke fever when they travel through the circulation (though there is some disagreement among experts on this point) and are sensed by the brain. Fever dramatically enhances the actions of many components of the immune response, including the ability to generate memory; it is not a bad thing and you do NOT need to treat a fever unless it is causing you significant discomfort. As Professor Shane Crotty explained in a great tweetorial here, your immune system has to work for its memory (gains!). It’s not unlike your muscles being sore after an intense workout. That said, while this is true broadly at the population level, at the individual level, examination of immune responses to vaccines does not show a simple trend between the magnitude of the response and the reactogenicity of the vaccine within the individual. In other words, if you get a vaccine and don’t have these uncomfortable effects, you should not take that as evidence that the vaccine was ineffective.

More rigorously, there are evolutionary theories that suggest that pro-inflammatory cytokines (especially if a fever occurs) help to mediate so-called sickness behaviors. It’s thought that sickness behaviors evolved to divert our energy from anything that would be unproductive to our recovery. Inflammation also makes us more prone to social withdrawal, i.e. isolation (which is intriguing as it’s easy to see how this helps from a public health lens but unclear how such a reflex may have evolved), and also triggers fatigue, sleep changes, decreased appetite, and other changes. In particular, sleep seems to have a complex relationship with the immune system, and it’s been shown that sleep actually helps to support the normal function of the immune system (reviewed in a very high level of detail here) and poor sleep after a vaccine has been shown previously to be able to reduce efficacy.

Managing Vaccine Reactogenicity

Reactogenicity is a problem not simply because it is annoying or disruptive, but because the administration of a vaccine that can make patients feel ill undermines the trust between the patient and the clinician and can make them less inclined to seek care, or even develop a fear of the doctor or medical systems as a whole. Thus there is good cause to consider effective strategies to manage vaccine reactogenicity. The WHO has a position paper published in 2015 detailing effective strategies for this. Guidances include:

• Using neutral language when administering the vaccine e.g. “here I go” as opposed to “here comes the sting”
• Avoiding deceptive language e.g. “It will only hurt for a second”
• Avoid aspirating the injection site
• When multiple vaccines need to be given, they should be given in order of increasing painfulness
• For adults: distraction e.g. through breathing exercises is advised.
• Avoid taking pain-relievers i.e. NSAIDs or acetaminophen before and during vaccination, as this can reduce the efficacy of the vaccine. However, there is general consensus is that they can be taken after for management of reactogenicity symptoms.

In addition, if available, topical anesthetics to the injection site, especially for children, can be helpful. In children, virtual reality distraction has been implemented in some practices during vaccination. In general, no management is required of injection site reactions, though ice can be applied for pain, swelling, and redness if it becomes too bothersome. You should contact your healthcare provider regarding any concerns you have following a vaccination.

References

1. Administering Vaccines: Dose, Route, Site, and Needle Size. Immunize.org. [accessed 2020 Dec 11]. https://www.immunize.org/catg.d/p3085.pdf.
2. Besedovsky L, Lange T, Haack M. 2019. The sleep-immune crosstalk in health and disease. Physiol Rev. 99(3):1325–1380.
3. Blatteis CM, Sehic E, Li S. 2000. Pyrogen sensing and signaling: old views and new concepts. Clin Infect Dis. 31 Suppl 5(Supplement_5):S168–77.
4. Eisenberger NI, Moieni M, Inagaki TK, Muscatell KA, Irwin MR. 2017. In sickness and in health: The co-regulation of inflammation and social behavior. Neuropsychopharmacology. 42(1):242–253.
5. Evans SS, Repasky EA, Fisher DT. 2015. Fever and the thermal regulation of immunity: the immune system feels the heat. Nat Rev Immunol. 15(6):335–349.
6. Gonzalez-Dias P, Lee EK, Sorgi S, de Lima DS, Urbanski AH, Silveira EL, Nakaya HI. 2020. Methods for predicting vaccine immunogenicity and reactogenicity. Hum Vaccin Immunother. 16(2):269–276.
7. Hervé C, Laupèze B, Del Giudice G, Didierlaurent AM, Tavares Da Silva F. 2019. The how’s and what’s of vaccine reactogenicity. NPJ Vaccines. 4(1):39.
8. Irwin MR. 2019. Sleep and inflammation: partners in sickness and in health. Nat Rev Immunol. 19(11):702–715.
9. Petousis-Harris H. 2008. Vaccine injection technique and reactogenicity — evidence for practice. Vaccine. 26(50):6299–6304.
10. Prather AA, Hall M, Fury JM, Ross DC, Muldoon MF, Cohen S, Marsland AL. 2012. Sleep and antibody response to hepatitis B vaccination. Sleep. 35(8):1063–1069.
11. Ray JJ, Schulman CI. 2015. Fever: suppress or let it ride? J Thorac Dis. 7(12):E633–6.
12. Reducing pain at the time of vaccination: WHO position paper — September 2015. 2015. Wkly Epidemiol Rec. 90(39):505–510.
13. Shingles Vaccination. 2020 Nov 4. Cdc.gov. [accessed 2020 Dec 11]. https://www.cdc.gov/vaccines/vpd/shingles/public/shingrix/index.html.
14. Weiner J, Lewis DJM, Maertzdorf J, Mollenkopf H-J, Bodinham C, Pizzoferro K, Linley C, Greenwood A, Mantovani A, Bottazzi B, et al. 2019. Characterization of potential biomarkers of reactogenicity of licensed antiviral vaccines: randomized controlled clinical trials conducted by the BIOVACSAFE consortium. Sci Rep. 9(1):20362.