Side Effects of COVID-19 Vaccine and Hesitancy

#### **Chapter 9**

## Side Effects of the COVID-19 Vaccines

*Irina Magdalena Dumitru*

#### **Abstract**

Vaccination against COVID-19 was one of the most important discoveries in the fight against the pandemic and saved millions of lives. As with any vaccine, side effects have been reported, but the benefit of vaccination is much more important and should be considered. The most common side effects are mild to moderate, especially at the injection site, as well as self-limiting; non–life-threatening systemic reactions and severe reactions after vaccination are rare. In this chapter, the author will describe all types of side effects related to COVID-19 vaccines, information obtained from Web of Science, PubMed, Medline, Embase, Cochrane Library, Centre for Disease Control Prevention (CDC), cdc.gov database, and Vaccine Adverse Event Reporting System (VAERS).

**Keywords:** COVID-19, vaccine, protection, side effects, allergic reactions

#### **1. Introduction**

The occurrence of side effects after vaccination is a normal phenomenon; most side effects are local reactions and systemic effects are usually rare [1].

The safety of COVID-19 vaccines has been closely monitored during clinical trials, but even now, during their use, both local and systemic adverse reactions occur immediately after administration and delayed reactions [1].

Several types of COVID 19 vaccines have been used or are being used (**Table 1**):

#### **2. Common side effects**

The most common local effects after vaccination are pain, redness, and swelling at the injection site [3]. In a study conducted in the Czech Republic, on 922 health workers, local pain was reported in 89.8% of cases, after the administration of Pfizer-BioNTech COVID-19 vaccine [4]. Side effects after the second shot may be more intense than the ones experienced after the first shot [3].

Tiredness, headache, muscle aches, chills, joint pain, and fever (more common after the second dose) were also reported [5].

In his paper published in 2021, Meo et al. [6] analyzed the most recent and eloquent data on the side effects of the 2 RNA vaccines, Pfizer-BioNTech COVID-19


*induce an immune response. 12molecules that closely resemble viruses, but are non-infectious because they contain no viral genetic material.*

#### **Table 1.**

*COVID-19 vaccines [2].*

and Moderna, data published in the Web of Science (Clarivate Analytics), PubMed, EMBASE, World Health Organization (WHO), Food and Drug Authorities (FDA) USA, Local Ministries, Health Institutes, and Google Scholar. It was found that the most common reactions caused by administration of the first dose vaccine of Pfizer-BioNTech COVID-19 were pain, swelling, redness, fever, fatigue, headache, chills, vomiting, diarrhea, muscle pain, joint pain, lymphadenopathy, shoulder injury, right axillary lymphadenopathy, paroxysmal ventricular arrhythmia, syncope, and right leg paresthesia [7]; and pain, swelling, redness at the site of vaccine, fever, fatigue,

**Figure 1.**

*Comparison between frequencies of adverse effects of Pfizer-BioNTech and Moderna vaccines [6–9].*

*<sup>2</sup>adenovirus serotype 26. 3 chimpanzee adenovirus ChAdOx1. 4 vaccine consisting of virus particles that have been grown in culture and then killed to destroy disease-producing capacity. 5 adenovirus serotype 26 for the first shot and serotype 5 for the second. 6 the vaccine that contains purified parts of the pathogen that are antigenic, or necessary to elicit a protective immune response. 7 adenovirus serotype 5. 8 contains purified parts of the pathogen that are antigenic. 9 subunit vaccines made from peptides. 10type of subunit vaccine which combines a weak antigen with a strong antigen as a carrier so that the immune system has a stronger response to the weak antigen. 11type of vaccine that transfects a specific antigen-coding DNA sequence into the cells of an organism as a mechanism to* 


#### **Table 2.**

*The most common reactions after administration of Pfizer-BioNTech, Moderna, Janssen, and Oxford-AstraZeneca vaccines [2].*

headache, chills, vomiting, arthralgia, myalgia, and urticaria after the first dose of Moderna vaccine (**Figure 1**) [7]. Moderate or severe reactions have been reported after the second dose of vaccine, and facial swelling and Bell's palsy have also been reported [8].

Also, the most common reactions after administration of the most commonly used vaccines are shown in the **Table 2** [2].

#### **3. Allergic reactions**

Most side effects were mild and moderate, and severe allergic reactions were rare [10]. In patients who have experienced severe side effects after receiving the first dose of mRNA vaccines, dose 2 has not been given. Also, no other dose was given to patients who experienced severe allergic reactions after COVID 19 Janssen or Oxford-Astra Zeneca vaccines [10].

Documented hypersensitivity to polyethylene glycol (PEG) is a contraindication to the COVID-19 Pfizer vaccine, severe allergic reaction has been observed in about 10 cases per million doses of vaccine administered [11].

According to the Center for Disease Control (CDC), the 15-minute postvaccination monitoring recommendation is certified by the fact that most allergic reactions *Side Effects of the COVID-19 Vaccines DOI: http://dx.doi.org/10.5772/intechopen.105668*

(71%) occur during this period, especially in patients with a history of allergic events (81%) [11].

Anaphylaxis after COVID-19 vaccination is rare with rates of 4.7 cases/million Pfizer-BioNTech vaccine doses administered and 2.5 cases/million Moderna vaccine doses administered [12]. In cases where anaphylaxis has been reported, it has occurred within the first 15 minutes of receiving the vaccine, especially at the first dose of vaccine, usually in people who have reported allergic reactions or anaphylaxis in their medical history [13].

#### **4. Myocarditis and pericarditis**

Myocarditis and pericarditis after COVID-19 vaccination are rare. Most cases have been reported after receiving Pfizer-BioNTech or Moderna (mRNA COVID-19 vaccines), particularly in male adolescents and young adults [14]. Most of them (95%) had mild or moderate manifestations, self-limiting in most cases, and did not require hospitalization for more than four days [15, 16]. Myocarditis has been reported more often after the second dose, usually within a week of vaccination [14].

According to the Vaccine Adverse Event Reporting System (VAERS), a significant number of cases of myocarditis have been reported in young people, after the administration of mRNA vaccine, especially the second dose, with favorable evolution under specific treatment and hospitalization [17].

Related to the age group, most cases were reported in young people in the 16–17 age group (105.9 cases per one million doses) [17], followed by the 12–15 age group (70.7 cases per one million doses) and 18–24 age group (52.4 cases per million doses) [17].

In the study published in August 2021 by Diaz et al., myocarditis occurred a median of 3.5 days (IQR, 3.0–10.8 days) after mRNA vaccination, the median age was 36 years (IQR, 26–48 years), all were discharged after a median of 2 days (IQR, 2–3 days), and there were no readmissions or deaths [18].

Pericarditis developed especially after the second immunization, median onset was 20 days (IQR, 6.0–41.0 days) after the vaccination, median age was 59 years (IQR, 46–69 years median stay in hospital was 1 day (IQR, 1–2 days), no deaths were reported [18].

#### **5. Thrombosis with thrombocytopenia syndrome (TTS)**

Thrombosis with thrombocytopenia syndrome (TTS) has been associated with the administration of the Janssen COVID-19 vaccine [19]. TTS is rare and has occurred in approximately 4 cases per one million doses administered [19]. A review of reports indicates a causal relationship between the Janssen COVID-19 vaccine and TTS [20, 21].

The following features were found in relation to TTS [20, 21]:


Venous thrombosis risk factors in U.S. TTS cases following Janssen COVID-19 vaccination are [20, 21]: obesity (46%), hypertension (30%), diabetes (13%), and systemic estrogen therapy (6%).

Thrombotic adverse events have also been reported following the administration of the Oxford-AstraZeneca COVID-19 vaccine, especially in younger women [19, 22]. Analysis of VigiBase reported embolic and thrombotic events after vaccination with Oxford-AstraZeneca, found a related incidence of 0.21 cases per 1 million vaccinated-days [23].

The following characteristics were found in cases with TTS in connection with Astra Zeneca COVID-19 vaccination [19]:


### **6. Guillain-Barré Syndrome (GBS)**

Guillain-Barré syndrome (GBS) in people who have received the Janssen COVID-19 vaccine is a very rare side effect and was reported during the 42 days following vaccination, especially in men ages 50 years and older [24].

Based on a recent analysis of data from the Vaccine Safety Datalink, the rate of GBS was 11 times higher following Janssen COVID-19 vaccination compared to Pfizer-BioNTech or Moderna (mRNA COVID-19 vaccines) [25].

In a study, conducted by Miguel García-Grimshaw and published in August 2021, on more than 3 million people who received mRNA vaccines, GBS was very rare, with incidence of 0.18/100,000 administered doses, within 30 days from first dose vaccine administration [26]. No cases were reported after second dose administration [26]. The presence of a concomitant trigger in most of our cases suggests a lack of mechanistic connection between mRNA vaccines and GBS [26].

#### **6.1 Delayed type reactions**

Delayed hypersensitivity reactions after the administration of vaccines for COVID-19 have been reported, a median of 7 days after the first vaccine dose, mainly after administration of mRNA vaccines [27]. Delayed large local reactions were noted as well urticaria, morbilliform eruptions, erythromelalgia, erythema multiforme, vasculitis, petechiae, pityriasis-rosea-like exanthems, or persistent maculopapular exanthema [28, 29]. Angioedema and liver damage were also described [28, 29].

#### **6.2 Very rare side effects**

A number of very rare side effects have been reported with various vaccines:


#### **7. Conclusions**

COVID-19 vaccines are safe and effective; most side effects are mild and moderate and resolve in a few days. Severe reactions after vaccination are rare; however, the benefit of vaccination is much greater than the risk.

#### **Author details**

Irina Magdalena Dumitru Ovidius University of Constanta, Clinical Infectious Diseases Hospital Constanta, Romanian Academy of Romanian Scientists, Romania

\*Address all correspondence to: dumitrui@hotmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Safety of COVID-19 Vaccines. Available from: https://www.cdc.gov/ coronavirus/2019-ncov/vaccines/safety/ adverseevents.html?msclkid=b3bdd72ece f511eca44fe7d67523108e. [Accessed: May 22, 2022]

[2] List of COVID-19 vaccine authorizations. Available from: https:// en.wikipedia.org/wiki/List\_of\_COVID-19\_vaccine\_authorizations. [Accessed: May 22, 2022]

[3] Possible Side Effects After Getting a COVID-19 Vaccine. Updated January 12, 2022. Available from: https://www.cdc. gov/coronavirus/2019-ncov/vaccines/ expect/after.html. [Accessed: May 22, 2022]

[4] Abanoub R, Andrea P, Sameh A, Jitka K, Michal K, Miloslav K. Prevalence of COVID-19 vaccine side effects among Healthcare Workers in the Czech Republic. Journal of Clinical Medicine. 2021;**10**(7):1428

[5] Comirnaty: Product Information. European Medicines Agency (EMA). December 24, 2020. Available from: https://www.ema.europa.eu/en/ medicines/human/EPAR/comirnaty. [Accessed: May 22, 2022]

[6] Meo SA, Bukhari IA, Akram J, Meo AS, Klonoff DC. COVID-19 vaccines: Comparison of biological, pharmacological characteristics and adverse effects of Pfizer/ BioNTech and Moderna Vaccines. European Review for Medical and Pharmacological Sciences. 2021;**25**(3):1663-1669

[7] Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al. C4591001 clinical trial group. safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. The New England Journal of Medicine. 2020;**383**:2603-2615

[8] Centre for Disease Control Prevention (CDC). Information about the Pfizer-BioNTech COVID-19. Vaccine. 2022. Available from: https://www.fda.gov/ emergency-preparedness-and-response/ coronavirus-disease-2019-covid-19/ pfizerbiontech-covid-19-vaccine#additional. [Accessed: May 24, 2022]

[9] Centre for Disease Control Prevention (CDC). Information about the Moderna COVID-19. 2022. Available from: https:// www.fda.gov/media/144638/download. [Accessed: May 24, 2022]

[10] Vaccines for COVID-19. 2022. Available from: https://www.cdc.gov/ coronavirus/2019-ncov/vaccines/index. html. [Accessed: May 22, 2022]

[11] CDC COVID-19 Response Team. Allergic reactions including anaphylaxis after receipt of the first dose of Pfizer-BioNTech COVID-19 Vaccine - United States, December 14-23, 2020. MMWR. Morbidity and Mortality Weekly Report. 2021;**70**(2):46-51

[12] CDC. COVID-19 vaccination: Interim clinical considerations for use of mRNA COVID-19 vaccines currently authorized in the United States. 2021. Available from: https://www.cdc.gov/ vaccines/covid-19/info-by-product/ clinical-considerations.html. [Accessed: February 9, 2021]

[13] Shimabukuro T, Cole M, Su JR. Reports of anaphylaxis after receipt of mRNA COVID-19 vaccines in the US—December 14, 2020-January 18, 2021. Journal of the American Medical Association. 2021;**325**(11):1101-1102. DOI: 10.1001/jama.2021.1967

[14] Myocarditis and Pericarditis After mRNA COVID-19 Vaccination. 2022.

Available from: https://www.cdc.gov/ coronavirus/2019-ncov/vaccines/safety/ myocarditis.html. [Accessed: May 24, 2022]

[15] Heller J. Israel sees probable link between Pfizer vaccine and myocarditis cases. Reuters. 2021

[16] Kim HW, Jenista ER, Wendell DC, et al. Patients with acute myocarditis following mRNA COVID-19 vaccination. JAMA Cardiology. 2021;**6**(10):1196-1201. DOI: 10.1001/jamacardio.2021.2828

[17] Su JR, McNeil MM, Welsh KJ, et al. Myopericarditis after vaccination, vaccine adverse event reporting system (VAERS), 1990-2018. Vaccine. Jan 29, 2021;**39**(5):839-845. DOI: 10.1016/j. vaccine.2020.12.046

[18] Diaz G, Parsons GT, Sara K, Gering SK, Meier AR, Ian V, et al. Myocarditis and pericarditis after vaccination for COVID-19. Journal of the American Medical Association. 2021;**326**(12):1210-1212. DOI: 10.1001/jama.2021.13443

[19] Cines DB, Bussel JB. SARS-CoV-2 vaccine–induced immune thrombotic thrombocytopenia. The New England Journal of Medicine. 2021;**384**(23):2254-2256

[20] Shay DK, Gee J, John RSJR, Myers TR, Marquez P, Liu R, et al. Safety monitoring of the Janssen (Johnson & Johnson) COVID-19 vaccine - United States. MMWR. Morbidity and Mortality Weekly Report. 2021;**70**(18):680-684

[21] See I, Su JR, Lale A, Woo EJ, et al. US case reports of cerebral venous sinus thrombosis with thrombocytopenia after Ad26.COV2 vaccination, March 2 to April 21, 2021. JAMA. 2021;**325**(24):2448-2456. DOI: 10.1001/jama.2021.7517

[22] Lai CC, Ko WC, Chen CJ, Chen PY, Huang YC, Lee PI, et al. COVID-19

vaccines and thrombosis with thrombocytopenia syndrome. Expert Review of Vaccines. 2021;**20**(8): 1027-1035

[23] Smadja DM, Yue QY, Chocron R, Sanchez O, Lillo-Le Louet A. Vaccination against COVID-19: Insight from arterial and venous thrombosis occurrence using data from VigiBase. The European Respiratory Journal. 2021;**58**(1)

[24] Janssen Letter Granting EUA Amendment. U.S. Food and Drug Administration (FDA). 2021. Reports of adverse events following use of the Janssen COVID- 19 Vaccine under emergency use authorization suggest an increased risk of Guillain-Barré syndrome during the 42 days following vaccination. Available from: https:// www.fda.gov/emergency-preparednessand-response/coronavirus-disease-2019 covid-19/janssen-covid-19-vaccine. [Accessed: May 25, 2022]

[25] Selected Adverse Events Reported after COVID-19 Vaccination. Guillain-Barré Syndrome. Available from: https:// www.cdc.gov/coronavirus/2019-ncov/ vaccines/safety/adverse-events.html. [Accessed: May 24, 2022]

[26] García-Grimshaw M, Michel-Chávez A, Vera-Zertuche JM, Galnares-Olalde JA, Hernández-Vanegas LE, Figueroa-Cucurachi M, et al. Guillain-Barré syndrome is infrequent among recipients of the BNT162b2 mRNA COVID-19 vaccine. Clinical Immunology. 2021;**230**:108818

[27] McMahon DE, Amerson E, Rosenbach M, et al. Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: A registry-based study of 414 cases. Journal of American Academy of Dermatology. 2021;**9622**:00658

[28] Ackerman M, Henry D, Finon A, et al. Persistent maculopapular rash

*Side Effects of the COVID-19 Vaccines DOI: http://dx.doi.org/10.5772/intechopen.105668*

after the first dose of Pfizer-BioNTech COVID-19 vaccine. Journal of the European Academy of Dermatology and Venereology. 2021. DOI: 10.1111/jdv.17248

[29] Bogdano G, Bogdano I, Kazandjieva J, et al. Cutaneous adverse effects of the available COVID-19 vaccines. Clinics in Dermatology. 2021

[30] Rosenblum HG, Hadler SC, Moulia D, Shimabukuro T, John R, Su JR, et al. Use of COVID-19 vaccines after reports of adverse events among adult recipients of Janssen (Johnson &Johnson) and mRNA COVID-19 vaccines (Pfizer-BioNTech and Moderna): Update from the advisory committee on immunization practices— United States, July 2021. MMWR Morbidity and Mortality Weekly Reports. August 13, 2021;**70**(32):1094-1099. On August 10, 2021, this report was posted as an MMWR Early Release on the MMWR website (https://www.cdc.gov/ mmwr)

[31] Ng XL, Betzler BK, Testi I, et al. Ocular adverse events after COVID-19 vaccination. Ocular Immunology and Inflammation. Aug 18, 2021;**29**(6): 1216-1224. DOI: 10.1080/09273948.2021. 1976221. Epub 2021 Sep 24

[32] An Q-J, Qin D-A, Pei J-X. Reactive arthritis after COVID-19 vaccination. Human Vaccines & Immunotherapeutics. 2021;**17**(9):2954-2956. DOI: 10.1080/21645515.2021.1920274

[33] Rela M, Jothimani D, Vij M, Rajakumar A, Rammohan A. Autoimmune hepatitis following COVID vaccination. Journal of Autoimmunity. 2021;**123**:102688. DOI: 10.1016/j. jaut.2021.102688

[34] Jeong J, Choi HS. Sudden sensorineural hearing loss after COVID-19 vaccination. International Journal of Infectious Diseases. 2021;**113**:341-343. DOI: 10.1016/j. ijid.2021.10.025

[35] Kong J, Cuevas-Castillo F, Nassar M, Lei CM, Idrees Z, Fix WC, et al. Bullous drug eruption after second dose of mRNA-1273 (Moderna) COVID-19 vaccine: Case report. Journal of Infection and Public Health. 2021;**14**:1392-1394. DOI: 10.1016/j.jiph.2021.06.021

[36] Yoshifuji A, Ishioka K, Masuzawa Y, Suda S, Murata S, et al. COVID-19 vaccine induced interstitial lung disease. Journal of Infection and Chemotherapy. 2022;**28**(1):95-98. DOI: 10.1016/j.jiac.2021.09.010

#### **Chapter 10**

## Optic Neuritis Following COVID-19 Vaccination: Real-World Ophthalmic Presentation

*Madhurima Roy and Charuta Shrotriya*

#### **Abstract**

After being plagued by COVID-19 for nearly 2 years, the whole world wishes for little more than the complete eradication of the disease. Our country, India commenced the much-awaited vaccination drive in Jan 2021. Ophthalmic manifestations have appeared in many forms post-COVID, amongst which neuro-ophthalmic manifestations are infrequent. This is a short series of three cases that presented with optic neuritis (ON). On further inquiry, all had received the Covishield vaccine within 5–12 days before the presentation, with no history of COVID-positive RT-PCR. All patients improved after pulse steroid therapy and are still under follow-up. Nevertheless, it's hard to determine whether post-COVD vaccine ON is a coincidence or cause. This series highlights the importance of taking the history of recent vaccination, especially in patients presenting with ON in the COVID 19 pandemic era.

**Keywords:** COVID-19, covishield vaccine, post vaccine optic neuritis, adverse events, ocular manifestations

#### **1. Introduction**

Optic neuritis, a predominantly clinical entity that is typically characterized by a diminution of vision, loss of color vision, and painful eye movement, is an uncommon but serious consequence following vaccination. Vaccinations contributed to the eradication of many infectious diseases like smallpox, poliomyelitis, and measles in world history. Neurological events following vaccination such as seizures, encephalopathy, or GBS [1, 2], are not unheard of, with the earliest reports dating back to the late 19th century, following the development of neuroparalytic syndrome after Pasteur's rabies immunization [3]. The rapid development and availability of vaccination, ahead of an anticipated timetable, for relief from the COVID-19 pandemic, was an unprecedented and monumental accomplishment, which, consequently left the prospect and question of long-term safety open and ambiguous. A meta-analysis of five randomized, doubleblind, placebo-controlled trials of COVID-19 vaccine candidates noted that local and systemic adverse events reported were all mild to moderate and transient in nature [4]. Therefore, reporting an untoward outcome following vaccination is paramount

to establishing a safety threshold for widespread public usage. From January 2021 onwards, India commenced the much-awaited vaccination drive. Ophthalmic manifestations have appeared in many forms post-COVID, amongst which neuro-ophthalmic manifestations are infrequent. This review article presents a short series of three cases from the real-world scenario that presented with optic neuritis (ON), post-vaccination. On further inquiry, all had received the Covishield vaccine within 5–12 days just before the presentation, with no history of RT-PCR positive COVID infection. An improvement was noted in all the patients after the pulsed intravenous methylprednisolone therapy, as per the ONTT (Optic Neuritis Treatment Trial) study, and the patients are currently under follow-up. Although it's hard to determine whether post-COVID vaccine ON is a coincidence or cause, this series highlights the importance of taking the history of recent vaccination, especially in patients presenting with ON in the COVID 19 pandemic era. Reporting cases of adverse reactions that manifest after the vaccination is a challenging yet imperative task to allow for the sustained development and research of vaccines, which are safe and effective for public usage.

#### **2. Case descriptions**

A 27-year-old lady presented with an acute onset decrease in vision, which was progressive in nature and associated with mild peri-ocular pain, in the left eye (LE) for 5 days. She did not give a history of diabetes or hypertension. On examination, the best-corrected visual acuity (BCVA) was found to be 20/20 in the right eye (RE) and 20/200 in the LE, along with RAPD and color desaturation (3 out of 21 plates on the Ishihara chart) in the LE. Fundoscopy of the LE revealed a diffusely swollen optic nerve head (**Figure 1a**). Visual field examination with automated perimetry (AP) showed an enlarged blind spot (**Figure 1b**). On further probing, it was revealed that 9 days before the presentation, she had received her first dose of the Covishield vaccine. MRI of the brain and orbits (T2) revealed an enhancement of the left optic nerve head just behind the disc (**Figure 1c**). VEP showed a flat wave in the LE compared to the RE (**Figure 1d**) which led to a diagnosis of optic neuritis (ON) in the LE, for which a neurologist's opinion was sought. Hematological examination showed normal limits of ESR and CRP, and antibody titer (Ab): ANA, ANCA, MOG, NMO (Aquaporin4) was negative. The patient was administered intravenous methylprednisolone pulse therapy for 3 days, followed by an oral steroid, following which, there was an improvement in BCVA to 20/40 in LE and the fundus revealed a reduction in the swelling of the optic nerve head (**Figure 1e**).

A 48-year-old Indian woman came to the hospital with gradual and painless diminution of vision in the LE, for 3 days. Examination revealed a BCVA of 20/30 in the RE and 20/80 in LE, along with RAPD. On dilated fundoscopy, a swollen optic disc with blurred margins was discovered (**Figure 2a**). An OCT was done, which revealed peri-papillary swelling of the retina (**Figure 2b**). Examination of the visual fields showed an inferior arcuate defect (**Figure 2c**) and VEP showed delayed latency and decreased amplitude in LE (**Figure 2d**). On probing, it was revealed that 5 days before presentation, she had received the second dose of the Covishield vaccine. She did not have any systemic illness or history of preceding fever. A diagnosis of ON was made in LE, with indices such as ESR, CRP, MRI brain, and orbit found to be within normal limits. A neurologist's consultation was sought and intravenous methylprednisolone pulse therapy was started. On follow-up, it was found that the BCVA had improved to 20/30 in LE and AP also showed a marked improvement (**Figure 2e**).

*Optic Neuritis Following COVID-19 Vaccination: Real-World Ophthalmic Presentation DOI: http://dx.doi.org/10.5772/intechopen.106322*

#### **Figure 1.**

*(a) Fundus showing swollen optic disc with blurred margins in LE. (b) AP showing enlarged blind spot. (c) MRI brain and orbit showing enhancement of the left optic nerve. (d) VEP showing flat waves in LE. (e) Fundus picture showing reduced swelling of the disc on follow-up.*

#### **Figure 2.**

*(a) Fundus showing swollen optic disc with blurred margin in LE. (b) OCT showing peripapillary swelling of the retina. (c) AP revealing an arcuate defect in the inferior hemifield. (d) VEP showing delayed latency and decreased amplitude. (e) Follow-up AP showing improvement.*

**Figure 3.**

*(a and b) Fundus photo showing swollen optic disc with blurred margin in both eyes. (c) VEP showing bilateral flat waves. (d and e) AP showing bilateral generalized depression of field on presentation, with improvement on follow-up.*

A 40-year-old Indian gentleman presented with a diminution of vision in both eyes (BE) which was acute in onset and was accompanied by peri-ocular pain for 7 days. Further inquiry revealed that 12 days before presentation, he had received the first dose of the Covishield vaccine. Ocular examination showed that the BCVA was 20/200 in BE. Anterior segment examination was unremarkable except for a sluggishly reacting pupil in both eyes (BE). On dilated fundoscopy, BE showed indistinct and swollen optic disc margins (**Figure 3a** and **b**). Visual field examination revealed generalized depression of the visual fields in BE (**Figure 3d** and **e**). VEP showed flat waves in BE (**Figure 3c**). A diagnosis of bilateral ON was made. Hematological examination revealed that ESR and CRP were within normal limits. He was started on intravenous methylprednisolone pulse therapy for 3 days followed by oral steroids in a tapering fashion after a neurologist consultation. After treatment with steroids, the visual acuity improved to 20/30 in RE and 20/40 in LE. Serial AP revealed an improvement of the fields with an inferior arcuate defect (**Figure 3d** and **e**). MRI brain and orbit was requested on follow-up.

#### **3. Discussion**

We are living amid a pandemic, where along with various systems, COVID-19 also involves the eye, including both the anterior segment, in the form of conjunctivitis, episcleritis, and the posterior segment, in the form of vascular occlusion,

#### *Optic Neuritis Following COVID-19 Vaccination: Real-World Ophthalmic Presentation DOI: http://dx.doi.org/10.5772/intechopen.106322*

and maculopathy. Additionally, reports have been made of neuro-ophthalmic involvement in the form of ON, tonic pupil, and orbital involvement. COVID-19 is reported to involve nearly all systems from mild to life-threatening severe respiratory distress to even death [5]. They say necessity is the mother of all inventions, and true to the word, the COVID-19 pandemic has prompted a worldwide effort toward employing futuristic technology in the development of vaccinations at an expedited rate. COVID vaccines form a crucial step in controlling the pandemic, with over a hundred million vaccines administered since the commencement of the mass vaccination program in early December 2020. Studies and trials do not report any major safety concerns in phase 3 randomized trials [6] nor in prospective studies [7] with a reportedly minuscule number of serious neurological side effects of these novel vaccines [8, 9]. The COVID vaccine, like any other, can cause side effects including mostly low-grade fever or muscle aches, and rarely neurological events [10]. Ocular side-effects caused by vaccinations are widely studied in existing literature [11–15], and occurrence of facial nerve palsies [16], abducens nerve palsy [17], acute macular neuropathy [18–20], central serous retinopathy [21], thrombosis [22], uveitis [23, 24], multiple evanescent white dot syndrome (MEWDS) [25], Vogt-Koyanagi-Harada (VKH) reactivation [26] and Grave's disease [27] has been documented after administration of the COVID-19 vaccination. As early as 2 weeks following administration of the inactivated COVID-19 vaccination, 12 eyes of 9 patients suffered from various ocular conditions such as choroiditis, uveitis, keratitis, scleritis, acute retinal necrosis, and iridocyclitis as reported by Kunpeng et al. [28] Predominantly retinal adverse events, namely paracentral acute middle maculopathy (PAMM), acute macular neuropathy (AMN), and subretinal fluid were reported by Pichi et al., after Sinopharm COVID-19 vaccination in 7 patients [29]. In this case series, all patients presented with ON, which developed within 5–12 days (mean 8.6 days) of COVID-19 vaccination. ON following vaccination, though rare, is not unheard of. There is a certain level of ambiguity when it comes to the exact mechanism which causes ON, but an activation of the host's immune system, leading to widespread damage of the myelin sheath of the optic nerve by the host T cells, is a popularly accepted theory [30]. Any side effects after vaccination are reported to VAERS (Vaccine Adverse Event Reporting System), a passive surveillance system, by health care professionals, patients who are affected, and by the vaccine manufacturers directly. A majority of patients who suffered from ON after vaccination (229 of the reported 537 cases) were reportedly isolated events [31–33]. Predominantly reported post-vaccine ON was due to the influenza vaccine, followed by ON post HPV, HBV vaccine [34]. ON developing as early as 24 hours post MMR vaccination, had also been reported [35]. Sawalha et al. [36] reported a case of bilateral ON which occurred within a week of COVID-19 symptoms. Similarly, Zhou et al. reported another case within a few days of COVID-19 [37]. Although ON following vaccination is an uncommon side effect, safety concerns are required. Recently, following the COVID-19 mRNA vaccination, two cases of bilateral arteritic anterior ischemic optic neuropathy (AAION) and acute zonal occult outer retinopathy (AZOOR) were reported [38]. Another study reported an acute diminution of visual acuity and visual fields following the 2nd dose of Pfizer- BioNTech vaccine [39]. Following the first dose of the ChAdO\_1 COVID-19 vaccine, a 40-year-old lady with a history of remitting-relapsing MS complained of blurred vision which quickly deteriorated to complete blindness, as reported by Helmchen et al., which on further investigation was diagnosed as optic neuritis with AQP4-antibody-negative neuromyelitis optica spectrum disorders-like syndrome [40].

To date, Alvarez et al. provide the largest multi-national report after vaccination against SARS-CoV-2, where 38 out of 55 cases of ON were associated with the AstraZeneca vaccine, mostly with a negative history of neuro-inflammation [41]. There was also a recent case report of the development of acute thyroiditis and bilateral ON following the CoronaVac vaccine [42]. Most of the reviewed literature includes case reports and series (**Table 1**), and there are certain limitations with regards to ophthalmic assessment, the treatment that was initiated, the visual outcome, and a general underreporting of cases.

As per the existing literature, this is very likely the first reported series of ON from India, following COVID-19 vaccination, with no evidence of an active infection. The approved Covishield vaccination was administered to all three patients, following which, two of the patients developed ON after the first dose and one after the 2nd dose. None of the patients had a previous history of RT-PCR-positive COVID-19 infection. As per the current information, Covishield is a recombinant vaccine in which, the SARS-CoV-2 spike glycoprotein is encoded by a replication-deficient chimpanzee adenoviral vector, which initiates an immunological response upon administration. A majority of the side effects occur on the day of vaccination, within 6–8 hours, but they are mostly self-limiting and resolve within 2–3 days. ON has been shown to occur due to a dysimmunological process caused by B cells targeting the adenoviral vector [45]. Although a review of safety has shown that the vaccine is generally well-tolerated, the possibility of ON should be kept in mind. A way forward can be to ask to report any new visual symptoms early, following vaccination. In our


#### **Table 1.**

*Review of literature of development of Optic neuritis following COVID-19 vaccination.*

series, all three patients responded well to steroids, as per the proposed ONTT trial. Although it's hard to determine whether post-COVID vaccine ON is a coincidence or cause, this series highlights the importance of taking the history of recent vaccination, especially in patients presenting with ON in the COVID-19 pandemic era.

#### **4. Conclusion**

This case series from real-world evidence, although small, can serve as a precedent for the reporting of any further cases, to secure a foothold and build a foundation for a greater understanding of whether post-COVID-19 vaccine ON is consequential or coincidental. It is prudent to ask for a thorough history of not just SARS-CoV infection but also vaccination, in a patient presenting with ON, as per the established connection. A close follow-up should be maintained to detect demyelinating disease early, in such patients.

Key summary points


#### **Author details**

Madhurima Roy1 \* and Charuta Shrotriya2

1 Department of Retina and Vitreous, Susrut Eye Foundation and Research Centre, Kolkata, India

2 Department of Ophthalmology, Susrut Eye Foundation and Research Centre, Kolkata, India

\*Address all correspondence to: kutunandini@yahoo.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Agmon-Levin N, Kivity S, Szyper-Kravitz M, Shoenfeld Y. Transverse myelitis and vaccines: A multi-analysis. Lupus. 2009;**18**:1198-1204

[2] Karussis D, Petrou P. The spectrum of post-vaccination inflammatory CNS demyelinating syndromes. Autoimmunity Reviews. 2014;**13**:215-224

[3] Miravalle A, Biller J, Schnitzler E, Bonwit A. Neurological complications following vaccinations. Neurological Research. 2010;**32**:285-292

[4] Yuan P, Ai P, Liu Y, Ai Z, Wang Y, Cao W, et al. Safety, tolerability, and immunogenicity of COVID-19 vaccines: A systematic review and metaanalysis. medRxiv. 2020;**11**:20224998. DOI: 10.1101/2020.11.03.20224998

[5] Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockart S, et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. NEJM. 2020;**383**(27):260315

[6] Sen M, Honavar SG, Sharma N, Sachdev MS. COVID-19, and eye: A review of ophthalmic manifestations of COVID-19. Indian Journal of Ophthalmology. 2021 Mar;**69**(3):488

[7] Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: An interim analysis of four randomized controlled trials in Brazil, South Africa, and the UK. The Lancet. 2021;**397**(10269):99-111. DOI: 10.1016/ S0140-6736(20)32661-1

[8] Menni C, Klaser K, May A, Polidori L, Capdevila J, Louca P, et al. Vaccine side-effects and SARS-CoV-2 infection after vaccination in users

of the COVID Symptom Study app in the UK: A prospective observational study. The Lancet Infectious Diseases. 2021 Jul 1;**21**(7):939-949. DOI: 10.1016/ S1473-3099(21)00224-3

[9] Goss AL, Samudralwar RD, Das RR, Nath A. ANA investigates neurological complications of COVID-19 vaccines. Annals of Neurology. 2021;**89**(5):856-857. DOI: 10.1002/ana.26065

[10] Roman GC, Gracia F, Torres A, Palacios A, Gracia K, Harris D. Acute Transverse Myelitis (ATM): Clinical review of 43 patients with COVID-19 associated ATM and 3 post-vaccination ATM serious adverse events with the chAdOx1 nCoV-19 vaccine (AZD1222). Frontiers in Immunology. 2021;**12**:653786. DOI: 10.3389/fimmu.2021.653786

[11] Lu L, Xiong W, Mu J, Zhang Q, Zhang H, Zou L, et al. Neurological side effects of COVID-19 vaccines are rare. Acta Neurologica Scandinavica. 2021 Jul;**144**(1):111

[12] Baxter R, Lewis E, Fireman B, DeStefano F, Gee J, Klein NP. Casecentered analysis of optic neuritis after vaccines. Clinical Infectious Diseases. 2016;**63**:79-81

[13] Agarwal A, Garg D, Goyal V, Pandit AK, Srivastava AK, Srivastava MP. Optic neuritis following the antirabies vaccine. Tropical Doctor. 2020;**50**:85-86

[14] Van de Geijn EJ, Tukkie R, van Philips LA, Punt H. Bilateral optic neuritis with branch retinal artery occlusion associated with vaccination. Documenta Ophthalmologica. 1994;**86**:403-408

[15] Basilious A, Jivraj I, DeAngelis D. Acute unilateral ptosis and myositis

following the H1N1 influenza vaccine. Ophthalmic Plastic & Reconstructive Surgery. 2020;**36**:e16-e17

[16] Repajic M, Lai XL, Xu P, Bell's LA. Palsy after the second dose of Pfizer COVID-19 vaccination in a patient with a history of recurrent Bell's palsy. Brain, Behavior, & Immunity - Health. 2021 Oct 1;**25**(5):302-303. DOI: 10.1016/j. bbih.2021.100217

[17] Reyes-Capo DP, Stevens SM, Cavuoto KM. Acute abducens nerve palsy following COVID-19 vaccination. Journal of AAPOS. Oct 1;**25**(5):302-303. DOI: 10.1016/j.jaapos.2021.05.003

[18] Book BAJ, Schmidt B, Foerster AMH. Bilateral acute macular neuroretinopathy after vaccination against SARS-CoV-2. JAMA Ophthalmology. 2021;**139**(7):e212471. DOI: 10.1001/ jamaophthalmol.2021.2471

[19] Mambretti M, Huemer J, Torregrossa G, Ullrich M, Findl O, Casalino G. Acute macular neuroretinopathy following coronavirus disease 2019 vaccination. Ocular Immunology and Inflammation. 2021;**30**:1-4. DOI: 10.1080/09273948.202 1.1946567.30

[20] Michel T, Stolowy N, Gascon P, et al. Acute macular neuroretinopathy after COVID-19 vaccine. Journal of Ophthalmic Inflammation and Infection. 2021

[21] Fowler N, Mendez Martinez NR, Pallares BV, Maldonado RS. Acuteonset central serous retinopathy after immunization with COVID-19 mRNA vaccine. American Journal of Ophthalmology Case Reports. 2021;**23**:101136. DOI: 10.1016/j. ajoc.2021.101136

[22] Bayas A, Menacher M, Christ M, Behrens L, Rank A, Naumann M. Bilateral superior ophthalmic vein thrombosis, ischaemic stroke, and immune thrombocytopenia after ChAdOx1 nCoV-19 vaccination. Lancet. 2021;**397**(10285):e11. DOI: 10.1016/s0140-6736(21)00872-2

[23] Goyal M, Murthy SI, Annum S. Bilateral multifocal choroiditis following COVID-19 vaccination. Ocular Immunology and Inflammation. 2021;**3**:1-5. DOI: 10.1080/09273948.2021. 1957123

[24] Rabinovitch T, Ben-Arie-Weintrob Y, Hareuveni-Blum T, et al. Uveitis following the BNT162b2 mRNA vaccination against SARS-CoV-2 infection: A possible association. Retina. 2021 Dec 1;**41**(12):2462-2471. DOI: 10.1097/iae.0000000000003277

[25] Ramakrishnan MS, Patel AP, Melles R, Vora RA. Multiple evanescent white dot syndrome: Findings from a large Northern California Cohort. Ophthalmology Retina. 2021 Sep 1;**5**(9):850-854. DOI: 10.1016/j. oret.2020.11.016

[26] Papasavvas I, Herbort CP Jr. Reactivation of Vogt-Koyanagi- Harada disease under control for more than 6 years, following anti-SARS-CoV-2 vaccination. Journal of Ophthalmic Inflammation and Infection. 2021;**11**(1):21. DOI: 10.1186/s12348-021-00251-5

[27] Vera-Lastra O, Ordinola Navarro A, Cruz Domiguez MP, Medina G, Sanchez Valadez TI, Jara LJ. Two cases of graves' disease following SARS-CoV-2 vaccination: An autoimmune/ inflammatory syndrome induced by adjuvants. Thyroid. 2021 Sep 1;**31**(9):1436-1439. DOI: 10.1089/ thy.2021.0142

[28] Pang K, Pan L, Guo H, Wu X. Case report: Associated ocular adverse *Optic Neuritis Following COVID-19 Vaccination: Real-World Ophthalmic Presentation DOI: http://dx.doi.org/10.5772/intechopen.106322*

reactions with inactivated COVID-19 vaccine in China. Frontiers in Medicine. 2022:2928

[29] Pichi F, Aljneibi S, Neri P, Hay S, Dackiw C, Ghazi NG. Association of ocular adverse events with inactivated COVID-19 vaccination in patients in Abu Dhabi. JAMA Ophthalmology. 2021 Oct 1;**139**(10):1131-1135

[30] Shams PN, Plant GT. Optic neuritis: A review. International MS Journal. 2009;**16**(3):82-89

[31] Shimabukuro TT, Nguyen M, Martin D, DeStefano F. Safety monitoring in the vaccine adverse event reporting system (VAERS). Vaccine. 2015;**26**:335

[32] Roszkiewicz J, Shoenfeld Y. Vaccines and optic neuritis: Consequence or coincidence? Immunome Research. 2021;**17:1-2.3**(36):4398-4405

[33] Roszkiewicz J, Shoenfeld Y. Vaccines and optic neuritis: Consequence or coincidence? Immunome Research. 2021;**17**:1-2

[34] Michael ND, Jaffar TN, Hussein A, Hitam WH. Simultaneous bilateral optic neuritis following human papillomavirus vaccination in a young child. Cureus. 2018 Sep 24;**10**(9)

[35] Moradian S, Ahmadieh H. Early-onset optic neuritis following measles-rubella vaccination. Journal of ophthalmic & vision research. 2008;**3**(2):118

[36] Sawalha K, Adeodokun S, Kamoga GR. COVID-19-induced acute bilateral optic neuritis. Journal of Investigative Medicine High Impact Case Reports. 2020;**8**:2324709620976018

[37] Zhou S, Jones-Lopez EC, Soneji DJ, Azevedo CJ, Patel VR. Myelin oligodendrocyte glycoprotein antibody-associated optic neuritis and myelitis in COVID-19. Journal of Neuro-Ophthalmology. 2020 Sep 1

[38] Maleki A, Look-Why S, Manhapra A, Foster CS. COVID-19 recombinant mRNA vaccines and serious ocular inflammatory side effects: Real or coincidence? Journal of Ophthalmic & Vision Research. 2021;**16**(3):490

[39] Santovito LS, Pinna G. Acute reduction of visual acuity and visual field after Pfizer-BioNTech COVID-19 vaccine 2nd dose: A case report. Inflammation Research. 2021;**4**:1-3

[40] Helmchen C, Buttler GM, Markewitz R, Hummel K, Wiendl H, Boppel T. Acute bilateral optic/chiasm neuritis with longitudinally extensive transverse myelitis in longstanding stable multiple sclerosis following vector-based vaccination against the SARS-CoV-2. Journal of Neurology. 2021;**15**:1-6

[41] Alvarez LM, Ning Neo Y, Davagnanam I, Ashenhurst M, Acheson J, Abdel-Hay A, Alshowaeir D, Bakheet M, Balaguer O, Batra R, Braithwaite T. Post Vaccination Optic Neuritis: Observations From the SARS-CoV-2 Pandemic.

[42] Leber HM, Sant'Ana L, Konichi da Silva NR, Raio MC, Mazzeo TJ, Endo CM, et al. Acute thyroiditis and bilateral optic neuritis following SARS-CoV-2 vaccination with coronavac: A case report. Ocular Immunology and Inflammation. 2021;**16**:1-7

[43] Pawar N, Maheshwari D, Ravindran M, Padmavathy S. Ophthalmic complications of COVID-19 vaccination. Indian Journal of Ophthalmology. 2021 Oct;**69**(10):2900

[44] Elnahry AG, Asal ZB, Shaikh N, Dennett K, Abd Elmohsen MN,

Elnahry GA, et al. Optic neuropathy after COVID-19 vaccination: A report of two cases. The International Journal of Neuroscience. 2021:1-7

[45] Ng XL, Betzler BK, Testi I, Ho SL, Tien M, Ngo WK, et al. Ocular Adverse events After COVID-19 Vaccination. Ocular Immunology and Inflammation. 2021 Aug 18;**29**(6):1216-1224

#### **Chapter 11**

## Hesitancy for COVID-19 Vaccines and Its Implications for Routine Immunisation

*Mohan Kumar and V.L. Surya*

#### **Abstract**

Vaccine hesitancy is a continuum, conditional on confidence (on vaccine or healthcare authorities), complacency, structural or psychological constraints, calculation or evaluation, vaccination convenience, and aspects pertaining to collective responsibility. The present chapter documents hesitancy to COVID-19 vaccination; and elaborates on factors that contribute to both hesitancy (barriers and concerns) and acceptance (enablers) rates, disaggregated by populations. We also discuss the multimodal nature of the COVID-19 pandemic and its vaccine hesitancy-related implications on routine immunisation. The pandemic and related movement restrictions or other mitigation measures, partial or complete suspension of vaccination clinics or fear of COVID-19, stress, anxiety, and depression may have limited parents' access to avail routine immunisation vaccines for their children. Also, the impact of COVID-19 vaccine hesitancy is not limited to pandemic vaccines but may continue to extend to routinely recommended vaccines.

**Keywords:** COVID-19, vaccine hesitancy, routine immunisation, vaccine confidence

#### **1. Introduction**

Immunisation, a key primary healthcare component and an indisputable human right, is a public health achievement of the 20th century saving millions of lives every year. Vaccines and immunisation programmes currently prevent 3.5 to 5 million deaths every year from diseases like diphtheria, tetanus, pertussis, influenza, and measles. Also, they have prevented major epidemics of life-threatening diseases since the beginning of their widespread use in the 1900s underpinning global health security. Vaccines are now available to prevent more than 20 life-threatening diseases and are a vital tool in the battle against antimicrobial resistance.

The history of public concerns about and questioning vaccines, however, is as old as vaccines themselves. Modern communication systems have only accelerated anxieties about vaccine safety and its regulation. This has resulted in pockets of people who are reluctant or refuse recommended vaccination(s), or who chose to delay some vaccines. The SAGE Working Group on Vaccine Hesitancy documented that any delay in acceptance or refusal of vaccination despite the availability of vaccination services is

vaccine hesitancy. It is complex and context-specific, varying across time, place, and vaccines. Interestingly, the Working Group retained the term 'vaccine' rather than 'vaccination' hesitancy, although the latter more correctly implies the broader range of immunisation concerns [1].

It is important to monitor the reasons why a substantial number of people hesitate to receive recommended vaccinations. This allows identification of important trends over time and designing and evaluation strategies to address vaccine hesitancy and thereby increase vaccine uptake. Empirical and theoretical frameworks that assess vaccine hesitancy focus primarily on confidence in vaccines and the system that delivers them. It is essential to acknowledge that confidence covers trust in vaccines including concerns about vaccine safety, trust in healthcare workers delivering the vaccine, and in those making the decisions to approve of vaccines for a population. Vaccination behaviour can be explained by complacency (not perceiving diseases as high risk), constraints (structural and psychological barriers), the calculation (engagement in extensive information searching), and aspects pertaining to collective responsibility (willingness to protect others). These are the five main personal determinants for vaccine hesitancy [2]. To add to it would be vaccination convenience. The physical availability of vaccines, geographical accessibility, affordability and willingness-to-pay, ability to understand or comprehend that is, language and health literacy and ability of the immunisation services to appeal may affect vaccine uptake. In addition, the actual or perceived quality of the service and the degree to which vaccination services are delivered at a time and place within a cultural context that is convenient and comfortable may also affect the decision to be vaccinated and could lead to vaccine hesitancy.

Vaccine hesitancy is a continuum with those who accept all with no doubts and refuse all vaccines with no doubts as extremes (**Figure 1**). This may include a proportion who accept or completely refuse vaccines but are unsure. Between the extremes are those vaccine-hesitant individuals who accept some, delay or refuse some vaccines. While high levels of hesitancy lead to low vaccine demand, low levels of hesitancy do not necessarily mean high vaccine demand [3].

**Figure 1.** *Vaccine hesitancy continuum.*

#### **2. Determinants of vaccine hesitancy**

Provided that vaccine hesitancy is complex and context-specific it may be influenced by historic, socio-cultural, psychosocial, family, environmental, health system or institutional, economic, or political factors. Apart from these contextual factors, individual or group and vaccine or vaccination-specific concerns may also determine vaccine hesitancy. Taking about individual and group influences, they may arise from personal or social or peer perceptions of the vaccine (**Table 1**) [3].

#### **3. COVID-19 vaccine hesitancy**

COVID-19 vaccine hesitancy is real. In a meta-analysis that computed the overall COVID-19 vaccine acceptance rate across the US, the vaccine acceptance was as low as 12% and higher up to 91% [4]. Similarly, in a community-based sample of the American adult population, it was found that the likelihood of getting a COVID-19 immunisation was 52% very likely and 22% not likely or not, with individuals having lower education, income, or perceived threat of getting infected being more likely to report that they were not likely to not going to get COVID-19 vaccine (that is, vaccine hesitancy) [5]. A multi-country study of six Southeast Asian countries showed that the majority (84%) would accept COVID-19 vaccines. However, the variation between countries was significant with the lowest rates reported in Vietnam (27%) and the highest rates reported in Russia (72%) [6]. The disparities in interregional and inter-country (even within countries) COVID-19 vaccine hesitancy has been well documented. In a global cross-sectional study that included participants from seventeen countries across regions, it was found that participants from China (95.3%), Australia (96.4%), and Norway (95.3%) were most likely to get COVID-19 vaccination. However, participants from United States (29.4%), Japan (34.6%), and Iran (27.9%) were least likely to get vaccinated or in other words likely to be vaccine hesitant [7]. In a nationwide survey reported from India, only 30% of adults had no issue with the COVID-19 vaccine or vaccination [8]. This finding corroborates with the neighbouring nation Bangladesh where the reported prevalence of vaccine hesitancy was 46.2% [9]. The overall prevalence of COVID-19 vaccine hesitancy among Chinese adults was modest at 8.4% (95% CI, 8.09 to 8.72) for primary vaccination and 8.4% (95% CI, 8.07 to 8.70) for booster vaccination [10]. COVID-19 vaccine hesitancy has been particularly higher among older people (27.0%, 95% CI 15.1 to 38.9) [11].

#### **3.1 Quantifying COVID-19 vaccine hesitancy**

A literature search revealed few efforts aimed at quantifying vaccine hesitancy in the population [12, 13]. Firstly, the vaccine hesitancy index (VHI) was constructed using population characteristics aligned with factors identified by an Office for National Statistics (ONS) survey analysis; the factors included in the index were population under fifty, the proportion of Black or African or Caribbean ethnic population, children under five, population with less than degree level qualification and rental housing (social or private as a proportion of the total population) [14]. This was an improved version of the earlier published COVID-19 vulnerability index (VI) that considered income domain indicators and long-term illness [15].


#### **3.2 Predictors of COVID-19 vaccine hesitancy**

The data relating to the safety and efficacy of vaccines against COVID-19 are largely from high-income countries. In addition, the rapid pace of vaccine development has been highlighted in the literature as the primary reason for COVID-19 vaccine hesitancy. A COVID-19 vaccination acceptance and hesitancy survey including data from 15 survey samples covering 10 low- and middle-income countries (LMICs) in Asia, Africa, South America, Russia (an upper-middle-income country) and the United States reported that there was considerably higher willingness to take a COVID-19 vaccine in LMIC samples (mean 80.3%; median 78%; range 30.1%) compared with the United States (mean 64.6%) and Russia (mean 30.4%). The primary reason for acceptance was explained by interest in personal protection against COVID-19, whereas concerns in relation to side effects resulted in hesitancy [16]. It is, however, important to note that reported intentions may not always translate into vaccine uptake [17]. These findings corroborate a study conducted by Africa Centres for Disease Control and Prevention, in partnership with the London School of Hygiene and Tropical Medicine, in 15 African nations. More than three-fourths (79%) of respondents in Africa would be vaccinated against COVID-19 if it were deemed safe and effective. This may be explained based on lived experience in LMICs, where many vaccine-preventable infectious diseases are still a leading cause of morbidity and mortality, resulting in a higher perceived need for or value of vaccines [18]. However, in contrast, many people including medical professionals from high-income countries have not seen the devastating effects of these diseases in their respective countries. This is because they have successfully eliminated or eradicated numerous vaccine-preventable diseases. As a consequence resulting in altered risk calculations, complacency and limited collective responsibility about vaccination decision-making [18, 19]. In a survey among the United Kingdom (UK) adults that assessed their religious and political beliefs as well as their eagerness, willingness, and hesitance to take various global COVID-19 vaccines it was found that social media use does have an effect on perceived knowledge about vaccines as well as on vaccine hesitancy (especially Twitter!). People also express concerns over the trustworthiness of foreign vaccine production and testing protocols [20].

Evidence shows that 38%, 21%, 13%, and 11% variance in COVID-19 vaccine hesitancy can be explained by vaccine confidence, vaccine complacency, sociodemographic, and other psychological factors respectively [21]. Right-wing political affiliation, higher risk propensity, and less negative mental health effects of the COVID-19 pandemic were the principal sociodemographic and psychological determinants of COVID-19 vaccine hesitancy. Other sociodemographic determinants include younger age, women, race, and employment status. However, this particular study failed to examine the variance explained by vaccine convenience factors like availability, accessibility, affordability, willingness to pay, language, and health literacy [21]. Similarly, the willingness to vaccinate among Chinese adults was associated with gender (being women), higher levels of education, married residents, increased washing hands, never smoking, a higher score of health condition, increased wearing masks, higher level of convenient vaccination, increased social distance, disease risks outweigh vaccine risk, lower level of vaccine conspiracy beliefs, and a higher level of trust in doctor and developer [10].

In a study that assessed the intention to vaccinate for different effectiveness scenarios and side effects using the health belief model, it was found that the probability of rejecting a vaccine or indecision in relation to vaccine uptake were associated with

the severity of COVID-19. This includes, but not limited to, adverse side effects and effectiveness of the vaccine; decreased fear of contagion, perceived benefits including immunity, and the protection of oneself and the social environment; available information, specialists' recommendations; action signals, such as responses from ones' family and the government; and susceptibility, including the contagion rate per 1000 population. The vaccine scenarios used in the study revealed that the individuals preferred less risky vaccines in terms of fewer side effects, rather than effectiveness [22].

In a cross-sectional study that aimed at determining the predictors of COVID-19 vaccine hesitancy among pregnant women it was found that, vaccine hesitant women are younger and further along in pregnancy. COVID-19 vaccine hesitant pregnant women also reported hesitancy for influenza and Tdap vaccines. Vaccine hesitancy was associated with lack of information to take an informed decision, personal long term side effects, short and long term side effects on the pregnancy, and harmful ingredients in the vaccine [23].

In a qualitative analysis that explored the intention to receive or not receive COVID-19 vaccine among Malaysians using an integrated framework of theory of reasoned action and health belief model, it was found that the predictors of vaccine hesitancy were age, religious beliefs, subjective norms, susceptibility, attitude, and vaccine confidence or trust [24]. In contrast to the findings of a global survey from seventeen countries which reported increasing vaccine hesitancy with increase in age [7], this study reported that the vaccine hesitancy was higher among those young, primarily driven by perceived (low) risk of COVID-19. The study also stressed the importance of social influence; an individual is more likely to get vaccinated if one or the other in his/her closest circle is either vaccinated or intend to get vaccinated [24].

A population based cross-sectional study from Germany reported predictors of COVID-19 vaccine hesitancy among adults more than or equal to 18 years of age. Regression analysis showed that the odds of willingness to get vaccinated were lower for females in comparison to males; however, participants of older age group, higher education, health literacy, and adherence to preventive measures increased the odds of willingness to get vaccinated [25].

Vaccine hesitancy or say vaccine acceptance, be in at individual level or societal level is driven by complex factors. The Royal Society of Canada Framework (an adapted version of Hasnan and Tan framework) discusses COVID-19 vaccine acceptance as shown in **Figure 2**. The four major domains of factors that influence vaccine acceptance are immunisation knowledge (highlighting the importance of vaccine related reliable information, that is, easily accessible, up-to-date, and accurate tailored for each target group), healthcare workers, people in place (in accordance with the goal of the World Health Organisation Immunisation Agenda 2030) and the health care system (highlighting the role of immunisation programmes, health legislations and policies) [26]. Each of these major domains influence each other and none of these stand alone; the intersections are highlighted in white boxes. The blue circle illustrate the broader context under which each of the major domain is influenced, which includes, but not limited to, education, control of infection, communication, and communities [27, 28].

#### **4. Implications for routine immunisation**

The implications of the COVID-19 pandemic and its vaccine hesitancy against routine immunisation is multi-modal – one, the pandemic and related movement *Hesitancy for COVID-19 Vaccines and Its Implications for Routine Immunisation DOI: http://dx.doi.org/10.5772/intechopen.106362*

#### **Figure 2.**

*Framework of factors that influence vaccine acceptance.*

restrictions or other mitigation measures, partial or complete suspension of vaccination clinics or fear of COVID-19, stress, anxiety, and depression may have limited parents access to avail routine immunisation vaccines for their children [29, 30]. In a data triangulated from global, country-based, and individual-reported sources during the pandemic period, it was found that there was a decline in the number of administered doses of diphtheria pertussis tetanus-containing vaccine (DTP3) (33% fewer doses in April 2020) and the first dose of measles-containing vaccine (MCV1) (9–57% fewer doses) in the early part of 2020 [31]. The primary reason reported by WHO regional offices were substantial disruption to routine vaccination sessions, and in particular, related to interrupted vaccination demand and supply, including reduced availability of the health workforce. Similarly, a systematic review reported a decline or delay in vaccination at the time of the COVID-19 pandemic, highlighting the need for a sustained catch-up program, especially in low- and middle-income countries [32].

Secondly, the impact of COVID-19 vaccine hesitancy is not limited to pandemic vaccines but may continue to extend to routinely recommended vaccines. Though certain studies found increased vaccine confidence in parents for routine childhood vaccines as compared to the COVID-19 vaccine, certain studies highlight the concern of COVID-19 vaccine hesitancy rubbing off on routine immunisation vaccine hesitancy [33–36]. In a study that attempted to understand the impact of the pandemic on routine childhood vaccine hesitancy, it was found that the routine childhood vaccine hesitancy increased during the COVID-19 pandemic, mainly due to increased risk perception [37, 38].

It is the need of the hour to leverage COVID-19 vaccination awareness campaigns to include routine immunisation call-to-action messages [39]. Clear communication between public health authorities, providers, and the general public, and from providers to parents or caregivers on the value, safety, and necessity of routine immunisation will remain a critical piece to help alleviate concerns and address vaccine hesitancy. Engaging local leaders in the community may help resonate with public health messages related to the importance of routine vaccines, especially when the discussion around public health becomes tainted with political and/or

non-medical aspects. In this process of communication, it is important to maintain a delicate balance between what is known and acknowledging the uncertainties that remain. Easing societal restrictions where possible, taking the necessary steps to reach standard marketing authorization, offering a fixed monetary reward as an incentive, involving physicians in the vaccination campaign, and focusing on vaccine effectiveness while communicating risks clearly and transparently are recommended as measures to reduce vaccine hesitancy [40].

Overall, the strategies include offering pre-structured, pre-tested communication from community trusted sources such as healthcare providers, local representatives, and authorities. It should be ensured that they are culturally relevant, accessible and in multiple languages. It is important to improve the accessibility of population to vaccines and vaccine related information. This should be made possible through adoption of flexible, context specific delivery models. The success of these strategies are rested with training and education of those involved and community engagement. It is necessary to involve youth ambassadors, healthcare workers, community champions and faith leaders to raise knowledge and awareness on vaccinations. Vaccination of friends, relatives and household members should be celebrated; an approach of community immunity should be fostered; aided by locally developed action plans with a continuous, open, and transparent dialogue [41].

#### **5. Conclusion**

The implications of contextual factors, individual and group factors, vaccine, and vaccination related factors on vaccine hesitancy is long recognised. However, the additive or multiplicative, multi-modal implications of COVID-19 vaccine hesitancy on routine immunisation is less recognised. It is the need of the hour to leverage COVID-19 vaccination awareness campaigns to include routine immunisation call-toaction messages with effective monitoring and evaluation aided by implementation research strategies. The areas that should be strengthened to restore and maintain vaccine confidence includes trust in health care provider–patient encounters, public health messaging, vaccine mandates, diversity, inclusion, and representation in health sectors, and industry influence on health care.

*Hesitancy for COVID-19 Vaccines and Its Implications for Routine Immunisation DOI: http://dx.doi.org/10.5772/intechopen.106362*

#### **Author details**

Mohan Kumar1 \* and V.L. Surya2

1 Department of Community Medicine, KMCH Institute of Health Sciences and Research, Coimbatore, Tamil Nadu, India

2 Department of Microbiology, Coimbatore Medical College and Hospital, Coimbatore, Tamil Nadu, India

\*Address all correspondence to: kumar.mohan324@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Shen SC, Dubey V. Addressing vaccine hesitancy: Clinical guidance for primary care physicians working with parents. Canadian Family Physician. 2019;**65**(3):175-181

[2] Betsch C, Schmid P, Heinemeier D, Korn L, Holtmann C, Böhm R. Beyond confidence: Development of a measure assessing the 5C psychological antecedents of vaccination. PLoS One. 2018;**13**(12):e0208601. DOI: 10.1371/ journal.pone.0208601

[3] Mac Donald NE. Vaccine hesitancy: Definition, scope and determinants. Vaccine. 2015;**33**(34):4161-4164. DOI: 10.1016/j.vaccine.2015.04.036

[4] Yasmin F et al. COVID-19 vaccine hesitancy in the United States: A systematic review. Frontiers in Public Health Systematic Review. 2021;**9**:770985. DOI: 10.3389/fpubh.2021.770985

[5] Khubchandani J, Sharma S, Price JH, Wiblishauser MJ, Sharma M, Webb FJ. COVID-19 vaccination hesitancy in the United States: A rapid national assessment. Journal of Community Health. 2021;**46**(2):270-277. DOI: 10.1007/s10900-020-00958-x

[6] Marzo RR et al. Hesitancy in COVID-19 vaccine uptake and its associated factors among the general adult population: A cross-sectional study in six southeast Asian countries. Tropical Medicine and Health. 2022;**50**(1):4. DOI: 10.1186/s41182-021-00393-1

[7] Wong LP et al. COVID-19 vaccination intention and vaccine characteristics influencing vaccination acceptance: A global survey of 17 countries. Infectious Diseases of Poverty. 2021;**10**(1):122. DOI: 10.1186/s40249-021-00900-w

[8] Chandani S et al. COVID-19 vaccination hesitancy in India: State of the nation and priorities for research. Brain Behaviour, & Immunity Health. 2021;**18**:100375-100375. DOI: 10.1016/j. bbih.2021.100375

[9] Hossain MB et al. COVID-19 vaccine hesitancy among the adult population in Bangladesh: A nationwide cross-sectional survey. PLoS One. 2021;**16**(12):e0260821. DOI: 10.1371/journal.pone.0260821

[10] Wu J et al. COVID-19 vaccine hesitancy among Chinese population: A large-scale national study. Frontiers in Immunology Original Research. 2021;**12**:781161. DOI: 10.3389/ fimmu.2021.781161

[11] Veronese N et al. Prevalence of unwillingness and uncertainty to vaccinate against COVID-19 in older people: A systematic review and meta-analysis. Ageing Research Reviews. 2021;**72**:101489. DOI: 10.1016/j.arr.2021.101489

[12] Acharya R, Porwal A. "a vulnerability index for the management of and response to the COVID-19 epidemic in India: An ecological study," the lancet. Globalization and Health. 2020;**8**(9):e1142-e1151. DOI: 10.1016/ S2214-109X(20)30300-4

[13] Macharia PM, Joseph NK, Okiro EA. A vulnerability index for COVID-19: Spatial analysis at the subnational level in Kenya. BMJ Global Health. 2020;**5**(8):e003014. DOI: 10.1136/ bmjgh-2020-003014

[14] Daras K, Alexiou A, Rose TC, Buchan I, Taylor-Robinson D, Barr B. How does vulnerability to COVID-19 vary between communities in England? Developing a small area vulnerability

*Hesitancy for COVID-19 Vaccines and Its Implications for Routine Immunisation DOI: http://dx.doi.org/10.5772/intechopen.106362*

index (SAVI). Journal of Epidemiology and Community Health. 2021;**75**(8):729-734

[15] Welsh CE, Sinclair DR, Matthews FE. Static socio-ecological COVID-19 vulnerability index and vaccine hesitancy index for England. The Lancet Regional Health – Europe. 2022;**14**:100296. DOI: 10.1016/j. lanepe.2021.100296

[16] Solís Arce JS et al. COVID-19 vaccine acceptance and hesitancy in low- and middle-income countries. Nature Medicine. 2021;**27**(8):1385-1394. DOI: 10.1038/s41591-021-01454-y

[17] McEachan RRC, Conner M, Taylor NJ, Lawton RJ. Prospective prediction of health-related behaviours with the theory of planned behaviour: A meta-analysis. Health Psychology Review. 2011;**5**(2):97-144. DOI: 10.1080/ 17437199.2010.521684

[18] "COVID 19 Vaccine Perceptions: A 15 country study." Avaialble from: https://africacdc.org/download/covid-19-vaccine-perceptions-a-15-countrystudy/. [Accessed: June11, 2022].

[19] Machingaidze S, Wiysonge CS. Understanding COVID-19 vaccine hesitancy. Nature Medicine. 2021;**27**(8):1338-1339. DOI: 10.1038/ s41591-021-01459-7

[20] Bullock J, Lane JE, Shults FL. What causes COVID-19 vaccine hesitancy? Ignorance and the lack of bliss in the United Kingdom. Humanities and Social Sciences Communications. 2022;**9**(1):87. DOI: 10.1057/s41599-022-01092-w

[21] Gerretsen P et al. Individual determinants of COVID-19 vaccine hesitancy. PLoS One. 2021;**16**(11):e025 8462-e0258462. DOI: 10.1371/journal. pone.0258462

[22] Cerda AA, García LY. Hesitation and refusal factors in Individuals' decision-making processes regarding a coronavirus disease 2019 vaccination. Frontiers in Public Health, Original Research. 2021;**9**:626852. DOI: 10.3389/ fpubh.2021.626852

[23] Sutanto M, Hosek MG, Stumpff S, Ramsey PS, Boyd A, Neuhoff BK. Predictors of COVID-19 vaccine hesitancy and top concerns in pregnant women at a South Texas clinic [A128]. Obstetrics & Gynecology. 2022;**139**:37S-38S

[24] Ng JWJ, Vaithilingam S, Nair M, Hwang L-A, Musa KI. Key predictors of COVID-19 vaccine hesitancy in Malaysia: An integrated framework. PLoS One. 2022;**17**(5):e0268926. DOI: 10.1371/ journal.pone.0268926

[25] Umakanthan S, Lawrence S. Predictors of COVID-19 vaccine hesitancy in Germany: A crosssectional, population-based study. Postgraduate Medical Journal. 2022. DOI: 10.1136/postgradmedj-2021-141365. Available from: https://pmj.bmj. com/content/early/2022/02/02/ postgradmedj-2021-141365

[26] Dubé E, MacDonald NE. COVID-19 vaccine hesitancy. Nature Reviews Nephrology. 2022;**18**(7):409-410. DOI: 10.1038/s41581-022-00571-2

[27] Hasnan S, Tan NC. Multi-domain narrative review of vaccine hesitancy in childhood. Vaccine. 2021;**39, 1**(14):1910-1920. DOI: 10.1016/j.vaccine. 2021.02.057

[28] MacDonald NE et al. Royal society of Canada COVID-19 report: Enhancing COVID-19 vaccine acceptance in Canada. FACETS. 2021;**6**:1184-1246. DOI: 10.1139/facets-2021-0037

[29] Mansour Z et al. Impact of COVID-19 pandemic on the utilization of routine immunization services in Lebanon. PLoS One. 2021;**16**(2):e0246951. DOI: 10.1371/ journal.pone.0246951

[30] Rodríguez-Hidalgo AJ, Pantaleón Y, Dios I, Falla D. Fear of COVID-19, stress, and anxiety in university undergraduate students: A predictive model for depression. Frontiers in Psychology, Original Research. 2020;**11**:591797. DOI: 10.3389/fpsyg.2020.591797

[31] Shet A et al. Impact of the SARS-CoV-2 pandemic on routine immunisation services: Evidence of disruption and recovery from 170 countries and territories. The Lancet Global Health. 2022;**10**(2):e186-e194. DOI: 10.1016/S2214-109X(21)00512-X

[32] SeyedAlinaghi S et al. Impact of COVID-19 pandemic on routine vaccination coverage of children and adolescents: A systematic review. Health Science Reports. 2022;**5**(2):e00516. DOI: 10.1002/hsr2.516

[33] Temsah M-H et al. Parental attitudes and hesitancy about COVID-19 vs. routine childhood vaccinations: A National Survey. Frontiers in Public Health Original Research. 2021;**9**:752323. DOI: 10.3389/fpubh.2021.752323

[34] Badur S, Ota M, Öztürk S, Adegbola R, Dutta A. Vaccine confidence: The keys to restoring trust. Human Vaccines & Immunotherapeutics. 2020;**16**(5):1007-1017. DOI: 10.1080/ 21645515.2020.1740559

[35] Olusanya OA, Bednarczyk RA, Davis RL, Shaban-Nejad A. Addressing parental vaccine hesitancy and other barriers to childhood/ adolescent vaccination uptake during the coronavirus (COVID-19) pandemic. Frontiers in Immunology.

2021;**12**:663074. DOI: 10.3389/fimmu. 2021.663074

[36] Saurish SMVA, Amoghashree MR, Narayanamurthy, Gopi A. "Did this pandemic trigger a spike in mothers′ hesitancy over their children's routine immunizations? -A cross sectional study." Clinical Epidemiology and Global Health. 2022;**15**:101023. DOI: 10.1016/ j.cegh.2022.101023

[37] He K, Mack WJ, Neely M, Lewis L, Anand V. Parental perspectives on immunizations: Impact of the COVID-19 pandemic on childhood vaccine hesitancy. Journal of Community Health. 2022;**47**(1):39-52. DOI: 10.1007/ s10900-021-01017-9

[38] Karafillakis E, Van Damme P, Hendrickx G, Larson HJ. COVID-19 in Europe: New challenges for addressing vaccine hesitancy. The Lancet. 2022;**399**(10326):699-701. DOI: 10.1016/ S0140-6736(22)00150-7

[39] MOC Ota, Badur S, Romano-Mazzotti L, Friedland LR. "impact of COVID-19 pandemic on routine immunization," (in eng). Annals of Medicine. Dec 2021;**53**(1):2286-2297. DOI: 10.1080/07853890.2021.2009128

[40] Stamm TA, Partheymüller J, Mosor E, Ritschl V, Kritzinger S, Eberl J-M. Coronavirus vaccine hesitancy among unvaccinated Austrians: Assessing underlying motivations and the effectiveness of interventions based on a cross-sectional survey with two embedded conjoint experiments. The Lancet Regional Health – Europe. 2022;**17**:100389. DOI: 10.1016/j.lanepe.2022.100389

[41] Razai MS, Chaudhry UAR, Doerholt K, Bauld L, Majeed A. Covid-19 vaccination hesitancy. BMJ. 2021;**373**:n1138. DOI: 10.1136/bmj.n1138

### *Edited by Ibrokhim Y. Abdurakhmonov*

*COVID-19 Vaccines - Current State and Perspectives* provides the reader with the latest overview and opinions on the current state of the art in COVID-19 vaccines, as well as future prospects. The challenges covered include novel vaccine development for the emerging variants of concern (VOCs), vaccine side-effects with real-world examples, population hesitancy, and country experiences with COVID-19 vaccine development, clinical trialing and mass vaccination. Chapters discuss new opinions and directions on the repurposing of existing traditional vaccines with a wide spectrum of action and new platforms for fast-tracked vaccine production and approvals.

Published in London, UK © 2023 IntechOpen © ivandan / iStock

COVID-19 Vaccines - Current State and Perspectives

COVID-19 Vaccines

Current State and Perspectives

*Edited by Ibrokhim Y. Abdurakhmonov*