Efficacy, Safety and Immune Reactions Associated with COVID-19

Vaccines

Yuanlin Guo

Overseas Education College, Nanjing Tech University, Nanjing, Jiangsu, 210036, China

Keywords: COVID-19, SARS-Cov-2, Vaccines, Side Effects, Safety.

Abstract: COVID-19 is a disease caused by the SARS-CoV-2 virus that has spread into an worldwide pandemic. Quick

efforts into developing vaccines against SARS-CoV-2 took place, using both existing technologies or ones

newly released to the public. Side effects observed upon administration of previous vaccines or the unknown

associated with new vaccines have caused concern in large cohorts of population regarding their safety. In

this paper, we look with detail into the ingredients of existing COVID-19 vaccines and their side effects,

hoping to clear any concerns and claims that rose out of proportion. To obtain the presented data, we searched

and analyzed online reports and databases from vaccine developers and clinicians alike, as well as research

articles that covered the potential side effects of specific vaccine ingredients. Our research indicates that

existing vaccines against COVID-19 are safe for most of the population, with very small percentages of severe

side effects associated with it. The side effects of the vaccines largely outweigh the potential complications

arising from SARS-CoV-2 infection. Long term clinical trials for safety and efficacy are currently underway

to monitor any potential long term side effects.

1 INTRODUCTION

COVID-19 is a disease caused by the SARS-CoV-2

virus, that affects the respiratory system and a

multitude of other organs. It has a mortality rate of

around 2%, having caused about 4 million deaths

worldwide, and 200 million infections as of July

2021. SARS-CoV-2 virus has a surface spike protein

S that binds to the angiotensin converting enzyme II

(ACE2) in human cells, allowing the virus particle to

fuse with the host cell membrane and enter via

endocytosis. Currently, there is no approved

treatment that effectively reverses the course of

disease. As such, vaccines became a strong bet in the

fight against SARS-CoV-2. Several countries have

rushed to manufacture vaccines against the virus in

record times, starting in 2020 and as of July 2021, 20

vaccines against COVID-19 were approved

worldwide in different countries and 900 million

people have been vaccinated worldwide. (Vaccine

Tracker.2021)

With the development of new vaccines—some

with technology never used before in clinical

settings—several concerns about its safety profile

https://orcid.org/0000-0001-9721-0298

were raised. These concerns arise at times from

unfounded or false information from less reliable

sources, and leads to many individuals not taking the

vaccine, potentially increasing the spread of the

pandemic. In this article, we explored the possible

side effects and allergic reactions based on single

vaccine ingredients as well as complete vaccine

formulations. We explore and compare the current

vaccines against COVID-19, safety data, and

potential for immune reactions based on their

ingredients. These vaccines are described on Table 1,

showing the technology used for development and

their ingredients. In the following section, we

describe the different types of vaccines that are

developed against SARS-CoV-2.

2 COVID-19 VACCINE TYPES

2.1 Inactivated Virus Vaccines

Inactivated vaccines are developed by growing the

virus in a controlled laboratory environment using a

suitable cell culture as a host, and then deactivating it

314

Guo, Y.

Efﬁcacy, Safety and Immune Reactions Associated with COVID-19 Vaccines.

DOI: 10.5220/0011368800003438

In Proceedings of the 1st International Conference on Health Big Data and Intelligent Healthcare (ICHIH 2022), pages 314-324

ISBN: 978-989-758-596-8

using a variety of biological, chemical, or physical

methods. The inactivated virus offers a strong safety

profile but it will still be recognized by the immune

system, which makes antibodies against it. (Sanders,

Koldijk, and Schuitemaker 2014) Inactivated virus

vaccines have been used for a long time and other

types include vaccines against polio, hepatitis A,

rabies, influenza, tick-borne encephalitis, injected

typhoid, cholera, plague, pertussis, among others. The

viral material in inactivated vaccines does not

replicate, making them virtually impossible to cause

pathological effects due to infection.

2.2 Adenovirus Vector

Adenoviruses are originally nonenveloped double-

stranded DNA viruses. They can be modified to

deliver genetic material in human cells and as such

have been used for decades in gene therapy research.

Currently, there are several undergoing clinical or

preclinical trials using adenoviruses for vaccines

against different diseases and pathogens such as HIV,

Ebola, influenza, rabies, dengue, plasmodium

falciparum, mycobacterium tuberculosis. For

COVID-19 vaccines, these viruses were modified to

deliver DNA encoding the SARS-CoV-2 Spike

protein.

The adenovirus used in the vaccine lacks

replication because some genes necessary for

replication have been removed. Following

vaccination, the adenoviral vector enters the cell and

releases its genes, which are transported to the

nucleus, where the cellular machinery transcribes

messenger ribonucleic acid (mRNA) and translates it

into protein. Once released outside the cell, the

protein induces an immune response to generate

antibodies against it. (TATSIS, ERTL 2004)

2.3 mRNA Vaccines

mRNA molecules need to reach the cytoplasm or

endoplasmic reticulum ribosomes and be translated

into proteins, which is the concept of mRNA

vaccines. mRNA molecules can be encapsulated in

lipid nanoparticle (LNP) carriers to penetrate tissues

to facilitate the transfer of genetic information in host

cells, thereby initiating the synthesis of antigenic

proteins. (JACKSON, KESTER, CASIMIRO 2020)

In these vaccines, LNPs are used to protect RNA

against degradation, since this type of biomolecule is

more sensitive to degradation than DNA or proteins.

mRNA vaccines are new vaccine types that were not

tested before COVID-19. An advantage of these

vaccines when compared to adenovirus vector ones,

is that they can be produced in large scale more

quickly and at lower costs, since RNA encapsulation

in lipid nanoparticles is a more straight-forward

process. (PARDI, HOGAN, PORTER 2018)

2.4 Subunit Vaccines

Subunit vaccines are based on the direct delivery of

proteins, or parts of proteins, that mimic the ones in

SARS-CoV-2 and trigger an immune response to

these antigens. These vaccines are designed so that

their antigens lack pathogen-associated molecular

patterns (PAMPs) required by the host immune

system to recognize the antigen, reducing the

immunogenic potential of this vaccine approach.

(NIH 2019)

A potential problem with subunit vaccines is the

antigenic denaturation can occur, which can lead to

the production of different antibodies that do not

recognize the pathogen. This could potentially lead to

the protein binding to a different antibody than to a

specific antigen against the pathogen. Because the

antigens themselves normally only elicit a weak

immune response, when making this vaccine, non-

immunogenic materials are usually incorporated into

the vaccine formulation to improve the immune

response and enhance the efficacy of the vaccine.

These materials are called adjuvants.

Currently, a large number of protein subunit

vaccine candidates for SARS-CoV-2 are in human

clinical trials, with 2 on the market (see Table 1).

These candidates use a different immunogen, either

the whole Spike protein or a different form of its

receptor binding domain (RBD). RBD is the S protein

region that mediates the binding of the virus to the

ACE2 receptor of the target host cell.

Table 1: Approved covid-19 vaccines (as of July).

Vaccine name

Country of

origin

Trial Start

Date

Inactivated virus vaccines

CoronaVac China 2020-09-16

BBIBP-CorV China 2020-4-29

WIBP-CorV China 2020-04-11

Minhai Biotechnology

Co: SARS-CoV-2

Vaccine

China 2020-10-07

Covaxin India 2020-9-8

KoviVac Russia 2020-9-21

QazVac

Republic of

Kazakhstan

2020-8-28

COVIran Barekat Iran 2021-3-13

Adenovirus vector

Ad26.COV2.S

United

States

2020-6-30

Efﬁcacy, Safety and Immune Reactions Associated with COVID-19 Vaccines

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AZD1222

United

Kin

dom

2020-3-19

Ad5-nCoV

China 2020-9-26

Sputnik V COVID-19

vaccine

Russia 2020-6-18

Sputnik Light Russia 2021-1-19

Covishiel

India 2020-08-15

mRNA vaccines

mRNA-BNT162b2

United

States

2021-3-25

mRNA-1273

United

States

2020-2-25

Takeda: TA

-919 Japan 2020-11-21

Subunit vaccines

ZF2001 China 2020-08-16

iVacCorona Russia 2020-8-26

CIGB-66 Cuba 2020-12-7

3 SAFETY DATA

Initial clinical trials for the vaccines excluded

volunteers with history of allergic reactions, diabetes,

cancer, among other pathologies. Despite that, several

volunteers suffered adverse reactions upon vaccine

administration that resulted in temporary disability or

even death, although in very low numbers. This

prompted us to look at vaccine ingredients with a

potential to cause adverse effects.

In the sections below, we describe the safety and

efficacy data for some extensive used vaccines.

4 INACTIVATED VIRUS

VACCINES

4.1 CoronaVac

CoronaVac is an inactivated vaccine candidate

against COVID-19, From July 21 to December 16,

2020, Brazil recruited a total of 12,396 volunteers to

receive CoronaVac and placebo in a phase 3 clinical

trial. (PALACIOS, BATISTA, ALBUQUERQUE

2021) The most common adverse reactions in the

vaccine group were pain at the injection site (60.3%),

swelling (5.8%) and itching (4.2%); the most

common systemic adverse reactions were headache

(34.3%), fatigue (16.0%) and muscle pain (11.7%).

Among the 4,953 people, 14 days after the second

vaccination, 85 cases of symptomatic infection were

detected; among 4870 people in the placebo group,

168 cases of symptomatic infection were observed.

Therefore, the effective rate of Coronavac was

determined to be 50.7%. Fourteen days after

vaccination, the effective rate of preventing cases

where minimal medical intervention was required is

83.7%, and the effective rate of preventing moderate

to severe disease was determined to be 100%. All

severe cases (6 cases) are in the placebo group. There

are mainly three new coronavirus strains in Brazil,

namely B.1.1.28, P.1 and P.2. The first one is wild

type, and the latter two are variants. The main variant

of the institute in the region is P.2 The neutralizing

activity ratios of 45 volunteers' serum to B.1.1.28, P.1

and P.2 were 32 (71.1%) and 31 (68.9%),

respectively. In 36 people (80.0%), the study found

that the sera of the vaccinators had a consistent

neutralizing effect on all these variants. Overall,

Coronavac seems to be well tolerated.

4.2 BBIBP-CorV

BBIBP-CorV is a vaccine based on inactivated viral

particles. This candidate vaccine was developed by

Sinopharm Wuhan Institute of Biological Products

and the China Center for Disease Control and

Prevention. Two different SARS-CoV-2 strains,

WIV04 and HB02, were isolated from a patient at the

Jinyintan Hospital in Wuhan, China.

A large phase 3 clinical trial was conducted in

Asia, covering more than a dozen countries including

the United Arab Emirates (23.9%), India (14.0%),

Bangladesh (10.4%), China (9.8%), Pakistan (9.1%),

and others. The average age of volunteers was 36.1

years old, 84.4% were males, and 98.4% were 59

years old and below. Of the total 40,411 volunteers,

13,066 volunteers in WIV04 group, 13,086

volunteers in HB02 group, and 13,071 volunteers in

placebo group completed two injections. Within 1

week after vaccination, 44.2% (WIV04 group),

41.7% (HB02 group), 46.5% (placebo group) had

adverse reactions in each group, the most common of

which was injection site pain (24.3%, 19.4%, 27.9%

respectively) and headache (12.9%, 13.1%, 12.6%

respectively). As of December 20, 2020, after the

volunteers received the first injection (vaccine or

placebo), there were a total of 962 suspected cases.

After confirmation, there were 255 confirmed cases.

Among them, outside the monitoring period (the first

injection). In the 35th day afterwards, there were 113

confirmed cases, and within the monitoring period

(14 days after the second injection), there were 142

confirmed cases overall. (AL KAABI, ZHANG, XIA

2021) Among these 142 cases, 95 cases were in the

placebo group, 26 cases were in the WIV04 group,

and 21 cases were in the HB02 group. The calculated

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effective rate of the WIV04 vaccine is 72.8%, and the

effective rate of the HB02 vaccine is 78.1%.

4.3 WIBP-CorV

WIBP-CorV is another inactivated virus COVID-19

vaccine also developed by Sinopharm, for which the

viral particles were obtained from a different SARS-

CoV-2 source. JAMA published the phase III clinical

interim results of both BBIBP-CorV and WIBP-CorV

at the same time. (AL KAABI, ZHANG, XIA 2021)

Peer-reviewed results show WIBP-CorV is 72.8%

effective against symptomatic cases and 100%

against severe cases. The safety profile of the vaccine

is similar to BBIPP-CorV.

4.4 COVAXIN

COVAXIN, also known as BBV152, is a COVID-19

vaccine developed by Bharat Biotech in India in

collaboration with the Indian Medical Research

Council (ICMR), part of the National Institute of

Virology (NIV). The vaccine is manufactured using

viral particles that were grown on Vero cells and

subsequently inactivated. (Bharat Biotech 2021)

Phase 3 clinical trials of Covaxin were conducted

in different locations across India. 24,419 individuals

received two doses of BBV152 (n = 12,221) or

placebo (n = 12,198). There were 24 infections in the

vaccine group and 106 infections in the placebo

group, reported at least 2 weeks after the second dose.

The overall vaccine efficacy was 77.8%. The two-

dose vaccine was also 93.4% effective in those with

severe disease and 63% protective in those with

asymptomatic infection. The preprint reveals that in

those 60 years and older, the vaccine was 67.8%

effective, while in younger people, the effectivity was

determined to be 79.4%. Adverse events were below

1% in both groups, with the most frequent being

headache, followed by fever, fatigue and myalgia.

5 ADENOVIRUS VECTOR

5.1 Ad26.COV2.S (Janssen)

The Janssen COVID-19 vaccine is a recombinant,

replication-incompetent adenovirus serotype 26

(Ad26) vector vaccine that has been modified to

contain the gene for making a protein found on

SARS-CoV-2. Vaccination with the Janssen COVID-

19 vaccine consists of a single 0.6 mL dose

containing 5 × 10

viral particles, administered

intramuscularly. (LIVINGSTON, MALANI,

CREECH 2021)

In the phase 3 clinical trial “ENSEMBLE”

(clinicaltrials.gov accession number NCT04505722),

the per-protocol population included 19,630 SARS-

CoV-2–negative participants who received

Ad26.COV2.S and 19,691 who received placebo.

Three deaths reports occurred in the vaccine group

but no case was related to covid-19 and not attributed

to the vaccine, and 16 in the placebo group, 5 of

which were determined to be caused to COVID-19.

(SADOFF, GRAY, VANDEBOSCH 2021)

Vaccine recipients experienced a variety of

adverse symptoms. However, most were mild to

moderate and resolved 1–2 days after vaccination.

These are more common in people aged 18-59 than in

people over 60. Severe local or systemic reactogenic

symptoms were more common among vaccine

recipients (2.2%) than placebo recipients (0.7%). The

FDA identified injection site pain, hypersensitivity,

and systemic reactogenicity as three adverse events

associated with vaccination. No specific security

issues were found after analysis.

Out of more than 6.8 million doses administered,

embolic and thrombotic events were observed,

including six cases of a rare and severe type of blood

clot in individuals following administration. (CDC

2021) (FDA 2021) Cerebral venous sinus thrombosis

(CVST) was observed in combination with low levels

of blood platelets (thrombocytopenia) in these cases.

Medical and scientific teams at the FDA and CDC

examined available data and determined these events

were thrombosis-thrombocytopenia syndrome (TTS).

After a brief suspension, and following a safety

review by the CDC’s Advisory Committee on

Immunization Practices and the FDA have

determined that use of Janssen vaccine would resume

in the United States, effective April 23, 2021.

Ad26.COV2.S protected against moderate to

severe–critical COVID-19 with onset at least 2 weeks

after administration, where 116 cases in the vaccine

group vs. 348 in the placebo group were observed,

resulting in an efficacy of 66.9%. It was more

effective against severe Covid-19, with an incidence

of 76.7% at least 14 days after administration and

85.4% after 28 days .

Rare cases of the neurological disorder Guillain-

Barré syndrome have also been reported following

vaccination with the Janssen COVID-19 vaccine.

Although the chances of developing the condition are

low, they appear to be three to five times higher

among recipients of the Johnson & Johnson vaccine

than among the general population in the United

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States, although a causal relationship has not been yet

established. (VOYSEY, CLEMENS, MADHI 2021)

A single dose of Ad26.COV2.S protected against

symptomatic COVID-19 and asymptomatic SARS-

CoV-2 infection and was effective against severe–

critical disease, including hospitalization and death.

5.2 AZD1222 Vaxzevria

(Oxford-AstraZeneca)

The Oxford–AstraZeneca COVID-19 vaccine is a

replication-deficient Simian adenovirus vector.

Between April and November 2020, 23,848

participants were enrolled and 11,636 participants

(7,548 in the UK, 4,088 in Brazil) were included in

the primary efficacy analysis. (SCHULTZ,

SØRVOLL, MICHELSEN 2021) In participants who

received two standard doses, vaccine efficacy was

70.4%. From 21 days after the first dose, there were

ten cases hospitalized for COVID-19, all of which in

the placebo group; two were classified as severe

COVID-19, including one death. 175 severe adverse

events occurred in 168 participants, 84 events in the

ChAdOx1 nCoV-19 group and 91 in the control

group.

An article published on The New England Journal

of Medicine reported five cases of severe venous

thromboembolism in unusual sites and concomitant

thrombocytopenia that occurred 7 to 10 days after

vaccination with AZD1222. (EUROPEAN

MEDICINES AGENCY 2021) Four of the patients

had severe cerebral venous thrombosis with

intracranial hemorrhage, and the outcome for three of

them was fatal. Thrombotic thrombocytopenic

purpura and immune thrombocytopenic purpura are

not suspected because there was no hemolysis and the

platelet transfusion response was normal. What all

five patients have in common is high levels of PF4-

polyanion complex antibodies. The researchers

suggest that these cases represent vaccine-related

variants of spontaneous heparin-induced

thrombocytopenia, which they call vaccine-induced

immune thrombotic thrombocytopenia (VITT).

After a period of suspension, AZD1222

Vaxzevria was authorized in the EU to prevent

COVID-19 as the benefits of Vaxzevria outweigh its

risks in adults of all age groups from adverse events

including thrombosis in combination with TTS. The

frequency of TTS events was observed to be very rare

based on current reporting.

(LOGUNOV,

DOLZHIKOVA, SHCHEBLYAKOV 2021)

5.3 Sputnik V (Gam-COVID-Vac)

COVID-19 vaccine

The Gam-COVID-Vac vaccine, also known as

Sputnik V, was developed by a government-

sponsored team of cell microbiologists at the

Gamalaya Institute for Epidemiology and

Microbiology in Russia. Gam-COVID-Vac is based

on two human adenoviruses that contain a gene that

encodes the full-length spike protein S of SARS-

CoV-2 to stimulate an immune response.

In the Phase 3 trial, 21,977 adults were randomly

assigned to the vaccine group (n = 16,501) or the

placebo group (n = 5,476). From 21 days after the first

dose of vaccine, the day on which dose 2 was

administered, 16 (0.1%) participants in the vaccine

group and 62 (1,3%) in the placebo group were

confirmed to have COVID-19. Based on the second

interim analysis of data obtained 28 days after

administering the first dose, 7 days after the second

dose, vaccine efficacy was determined to be over 95%

42 days after the first dose, no life-threatening

adverse events were observed. (LOGUNOV,

DOLZHIKOVA, SHCHEBLYAKOV 2021)

The vaccine induced robust humoral and cellular

immune responses among individuals of all ages,

indicating a strong potential to prevent severe disease

in individuals over the age of 60.

An article published by Lancet claimed

discrepancies and substandard reporting of data on

the Sputnik V phase 3 trial. According to the trial

data, 35,963 individuals were screened and 21,977

individuals were randomized, but there disclosure as

to why 13,986 participants were excluded. The

authors also claim inconsistencies in the numerical

data related to vaccine efficacy. (BUCCI,

BERKHOF, GILLIBERT 2021)

6 mRNA VACCINE

6.1 Pfizer–BioNTech COVID-19

Vaccine (BNT162b2)

The Pfizer-BioNTech COVID-19 vaccine is

developed by the German company BioNTech, a

novel type based on encapsulated mRNA, that

encodes for the full SARS-CoV-2 Spike protein S.

In their press release issued on November 18

2020, Pfizer and BioNTech stated that the final

interim analysis data was 95% effective against

COVID-19 within a week of the candidate receiving

both inoculations. (Pfizer 2020) This data is based on

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the assessment of 43,448 participants, 170 of whom

developed COVID-19 during the assessment period.

Of these, 162 were in the placebo group and 8 were

in the vaccine candidate group. Vaccine efficacy is

consistent across age, gender, race, and ethnic

demographics. In addition, the efficacy observed in

the inoculated individuals over the age of 65 was over

94%. With regard to the safety of BNT162b2, no

serious safety issues have been reported. The more

frequent event compared to the placebo group is

fatigue. Based on these results, Pfizer and BioNTech

became the first company to submit a request for a

vaccine against SARS-CoV-2 to the FDA.

One ingredient found in mRNA vaccines of

particular concern for allergic reactions is a chemical

called polyethylene glycol (PEG). In mRNA

vaccines, PEG is used to coat mRNA molecules and

support their entry into cells. Since PEG is generally

not a component of previous vaccines, there is limited

information on its allergic effects.

An article on the journal Pediatrics reported 7

cases of clinical myocarditis or myopericarditis that

developed in 14- to 19-year-old males within 4 days

of receiving the second dose of the Pfizer-BioNTech

COVID-19 vaccine with no evidence of acute SARS-

CoV-2 infection. (MARSHALL, FERGUSON,

LEWIS 2021) These individuals developed chest pain

within 4 days after the second shot of the vaccine, and

developed fever before and after the onset. Further

studies need to be conducted to determine causation.

6.2 Moderna COVID-19 Vaccine

(mRNA-1273)

mRNA-1273 is a vaccine developed by the company

Moderna that uses mRNA that is translated into the

SARS-CoV-2 Spike protein to elicit an immune

response.

On November 18th 2020, Moderna published

their vaccine Phase 3 clinical study. 24,907 (82.1%)

participants who were considered to be at

occupational risk for acquiring the SARS-CoV-2

infection, of whom around 25% were healthcare

workers. This preliminary analysis was performed 14

days after the second vaccination and included 95

confirmed COVID-19 cases among the participants,

90 of which belonged to the group receiving placebo

and 5 cases belonged to the group receiving the

vaccine, resulting in a calculated efficacy of the

candidate vaccine of 94.5%. Furthermore, of the 11

cases that were considered severe, none were in the

vaccinated group, which indicates that mRNA-1273

may also prevent severe COVID-19.

As for the safety of mRNA-1273, mainly mild to

moderate events have been reported. The most

frequent severe adverse effects were soreness at the

injection site after the first dose (2.7%), and myalgia

(8.9%), arthralgia (5.2%), fatigue (9.7%). Overall,

these effects were described as short-lived. (Moderna

2020)

7 SUBUNIT VACCINES

7.1 ZF2001

ZF2001 is a protein subunit COVID-19 vaccine

developed by Anhui Zhifei Longcom. It uses a

traditional alum-based adjuvant with a long safety

profile.

50 participants in phase 1 trial, 900 participants in

phase 2 trial, randomly assigned to receive two doses

of placebo, 25 μg vaccine, or 50 μg vaccine, or three

doses of placebo, 25 μg vaccine, or 50 μg vaccine.

(YANG, LI, DAI 2021)

In the three doses of 25 μg vaccine group, the

most common local adverse reactions included pain

at the injection site (12%), swelling (14%), induration

(9%), redness (16%) and itching (19%). The most

common systemic adverse reactions in this group

included fever (8%), cough (1%), headache (2%) and

fatigue (0%). In general, most volunteers had no

adverse reactions or only minor adverse reactions. In

terms of humoral immunity, the seroconversion rates

of serum antibodies were 69% after the first injection,

and reached 100% 30 days after the second injection.

Notably, neutralizing antibodies were detected in

97% of the 25ug group. 14 days after the third

injection, neutralizing antibody titers of the 25ug

group exceeded those in the serum level of the

recovered patients. In terms of cellular immunity (T

cell response), the researchers performed an ELISpot

test on the peripheral blood of volunteers and

determined that both the 25μg group or the 50μg

group could induce moderate Th1 (IFN-γ and IL-2)

and Th2 (IL-4 and IL-5) responses after vaccination.

The data from Phase I/II suggest that ZF2001

offers a safe profile and strong immunogenicity.

Therefore, it was finally decided to use a three-dose

of 25ug (30 days between each injection) in the phase

3 clinical trial.

7.2 CIGB-66

CIGB-66 is a protein subunit COVID-19 vaccine

developed by the Center for Genetic Engineering and

Biotechnology in Cuba.

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On June 22,2021, official Cuban government

sources reported that the results of an initial study

involving 48,290 participants administered vaccines

in 3 doses, with a 2 weeks space. Result showed that

CIGB-66 had a 92.28% efficacy rate at preventing

symptomatic COVID-19. the analysis was based on

153 infection cases, including 11 in the vaccination

group and 142 in the placebo group.

8 VACCINE INGREDIENTS

WITH POTENTIAL ALLERGIC

SIDE EFFECTS

In the vaccines described above, some ingredients

have been known to cause allergic reactions. Below,

we discuss the known side effects associated with

each.

8.1 Beta-propiolactone

Beta-propiolactone (BPL) has been used for several

decades in different vaccines, such as the ones for

rabies. In 1987, a study by MC Anderson and

colleagues saw an association between urticarial

reactions and the rabies vaccine. (ANDERSON,

BAER, FRAZIER 1987) By looking at IgE and IgG

antibodies, researchers saw that besides developing

IgG against the subvirion, immunized individuals

also developed IgE and IgG to the BPL-Human serum

albumin used as adjuvant in the vaccine, which seems

to be the component that caused the strongest

reaction. Immunized subjects without urticaria had no

detectable IgE. The authors hypothesized that the

allergic reactions are mostly due to IgE antibodies,

since no fever, arthritis, lymphadenopathy or

nephritis were part of the symptoms. For the double

inactivated vaccine, beta-propiolactone, and human

serum albumin, most subjects with a urticarial

response to the booster had IgE. In contrast,

undetectable IgE in immunized subjects without

urticaria. A research article from 1987 also mentioned

urticaria as a common reaction to a rabies vaccine,

which also contained beta propiolactone. Studies

have shown that these responses are not caused by the

rabies virus antigens themselves, they are mostly

caused by the PBL-HSA complex. Notably, this

rabies vaccine response was very similar to that after

penicillin, suggesting an association with IgE

antibodies to penicillin metabolites that are haptens.

Apart from urticarial reactions, no adverse effects

have been associated with the use of beta-

propiolactone as an adjuvant, and therefore it seems

to be a safe ingredient in vaccine formulations.

8.2 Hydroxypropyl-β-cyclodextrin

Hydroxypropyl-β-cyclodextrin (HP-β-CD) is a cyclic

oligosaccharide of the cyclodextrin family that has

been used safely as an excipient for pharmaceutical

agents for decades. It is widely used to improve the

solubility of different compounds and it has been as a

excipient in pharmaceutical agents for several

decades. HP-β-CD as a vaccine adjuvant has shown

to induce IgG responses, but no IgE responses were

detected. Subcutaneous injection of solutions

containing HP-beta-CD is known to induce type I

interferon release and responses in Th2 cells, leading

to higher Ag-specific IgG titers, such as IgG1 and

IgG2c. However, no systemic proinflammatory

cytokine responses were detected. For this reason,

and for its high adjuvant activity, HP-β-CD is still

considered a safe adjuvant in vaccine formulations

with the main adverse event being diarrhea and there

have been no adverse events on kidney function.

(GOULD, SCOTT 2005)

8.3 Alum-based

Potassium alum, commonly named simply alum, is an

adjuvant with the formula KAl(SO

)

. Alum is well-

tolerated in a vast majority of cases and does not

usually induce clinically visible inflammatory

reactions in vaccinated subjects. It is known,

however, to cause nodules at the site of injection.

These nodules contain a large quantity of fibrin,

histone and host DNA and uric acid. It is

hypothesized that this release of intracellular

molecules may cause them to be recognized as

damage-associated molecular patterns (DAMPs).

(DESMET 2014) This release can trigger a

noninfectious inflammatory response by binding to a

pattern-recognition receptor. Aluminum-adjuvant-

containing vaccines are typically given over

relatively long intervals over a relatively short period

of time. Aluminum adjuvants immunotherapy should

take into consideration.

Aluminum salts are not currently used in

immunotherapy in the United States; however, they

are used in Europe as an immune stimulant. Some

researchers state that aluminum salts are mostly

irrelevant in immunotherapy. (TERHUNE, DETH

2014) Aluminum salts in allergy vaccines are known

to contribute to increased allergen-specific IgE, at

least in the 6 months following vaccine

administration. (JUTEL AKDIS 2011) In a 1972

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study, young healthy men experimentally immunized

with ryegrass pollen allergens and alum allergens

developed type I cutaneous hypersensitivity, specific

histamine-releasing, and passively transferable of IgE

antibodies. (MARSH, LICHTENSTEIN, NORMAN

1972)

8.4 Lipid Nanoparticles (LNPs)

The Pfizer-BioNTech vaccine includes 4 different

LNPs: cholesterol, ALC-0159 (2-[(polyethylene

glycol)2000]-N,N-ditetradecylacetamide),1,2-

distearoyl-sn-glycero-3-phosphocholine (DSPC) and

ALC-0315 [(4-hydroxybutyl)azanediyl)bis(hexane-

6,1-diyl)bis(2- hexyldecanoate)]. Cholesterol and

DSPC are also ingredients of the Moderna vaccine

and have been used in different pharmaceutical agents

such as Doxil. ALC-0315 is an aminolipid that helps

with mRNA compaction and is involved in its cellular

delivery and cytoplasmic release, which is thought to

happen by endosomal destabilization. The Moderna

vaccine also contains an ionizable aminolipid, the

formulation of which is not disclosed, but its thought

to be heptadecan-9-yl8-((2-hydroxyethyl)(6-oxo-6-

(undecyloxy)hexyl)amino)octanoate. ALC-0159 is

present in the Pfizer-BioNTech vaccine at levels <2

mol % and it helps with nanoparticle stabilization by

a steric mechanism through its (polyethylene glycol)

PEG moiety. The Moderna vaccine has a similar

compound named 1,2-dimyristoyl-rac-glycero-3-

methoxyPEG2000, which is also a PEGylated lipid.

These PEGylated lipids are thought to be the

causative agents in the few cases, anaphylaxis was

observed in individuals to whom the vaccines were

administered. Complement activation was initially

thought to be the cause of allergic reactions to

pegylated nanodrugs. (MOGHIMI 2018) Although

complement activation, was initially proposed as a

possible reaction to vaccines, it does not seem to be

the actual case, since anaphylaxis is very rare in both

Pfizer-BioNTech and Moderna vaccines. (GANSON,

POVSIC, SULLENGER 2016) In cases of

anaphylactic reactions to the PEGylated

nanomedicines, the mechanisms are still unknown.

Although most people have high levels of anti-PEG

IgG, adverse allergic reactions are not expected. This

may be due to differences in the properties of anti-

PEG antibodies, and individual differences in

susceptibility to antibody-triggered responses cannot

be ruled out. Still, the molecular basis of these

responses in humans remains unknown.

In responding individuals, hypersensitivity

reactions to LNP-based vaccines may be related to the

pre-existing pre-existence of presumed anti-PEG IgE,

in addition, the likely intradermal titers of anti-PEG

IgG are expected to be extremely low to explain the

hypersensitivity of vaccine recipients’ reaction.

(ZHOU, STONE, JAKUBOVIC 2021) Given the

widespread presence of PEG in cosmetics and daily

hygiene products, these products appear to be

frequently used by people who have displayed

allergic reactions to mRNA vaccines. It is reasonable

since that other IgEs that cross-react with a

heterogeneous set of allergenic determinants also

recognize LNP and LNP aggregates, trace

lipid/mRNA impurities. In addition, different

epitopes on vesicles and PEG-lipid micelles that may

coexist can also be recognized.

In summary, PEG 2000, which is used in the

Pfizer-BioNTech and Moderna vaccines to stabilize

lipid nanoparticles, is the only compound in these

vaccines reported to cause anaphylaxis.

8.5 Polysorbate80

Polysorbate 80 is another compound similar to PEG

2000 that is present in many food and drugs, as well

as the Oxford/AstraZeneca vaccine. Polysorbate 80

has is considered a potential trigger to anaphylactoid

reacts and it is thought to cross-react with PEG.

Polysorbate 80 is used as an excipient in many drugs

and some vaccines. It can also use as a food additive.

Polysorbate 80 is widely tolerated. However, it has

been thought to potentiate anaphylactic reactions.

(COORS, SEYBOLD, MERK 2005) The use of high

molecular weight PEGs in a large variety of

medications, cosmetic and cleaning products which

may lead to sensitization in a more susceptible

individuals.(STONE, LIU, RELLING 2019)

9 CONCLUSIONS

In this paper we reviewed the different types of

vaccines, their ingredients and the reactions

associated with them. With the fast spread of the

COVID-19 pandemic and the appearance of different

newly-developed vaccines against SARS-CoV-2,

many concerns were raised regarding the efficacy and

safety of these vaccines, particularly about the mRNA

ones based on newer technologies.

Although the ingredients in the vaccines herein

analyzed seem safe for most, care should still be

taken, and possible alternatives be sought. Virus-

inactivators such as beta-propiolactone seems to

cause allergic reactions in only a few subjects.

Although it has proved to be a very effective viral

inactivator, perhaps some non-immunological

Efﬁcacy, Safety and Immune Reactions Associated with COVID-19 Vaccines

321

alternatives such as radiation, formalin, or heat

inactivation could be considered to inactivate the

virus during the vaccine development stage. Several

vaccines inactivated using these methods have shown

great success in prevention. However, if a virulent

strain is used to produce the virus stock, inadequate

inactivation with formaldehyde can lead to several

issues. A number of children immunized with an

inactivated poliovirus vaccine preparation containing

inadequately inactivated Mahoney poliovirus

developed paralytic poliomyelitis. Furthermore, in

the 1960s, a formalin-inactivated RSV vaccine made

children sicker when they were exposed to natural

infections, resulting in several deaths. Likewise, an

inactivated measles vaccine was connected with an

unusual rash after exposure to the wild-type virus, a

reaction known as "atypical" measles. This brings us

back to the vaccines that do not use inactivated forms

of the virus, such as mRNA vaccines, where such

issues are not expected to occur. Despite very few

adverse reactions to beta-propiolactone, different

alternatives can be explored, mainly to reduce public

fear of vaccines and thus increase the number of

people getting vaccinated.

Concerning possible alternatives to alum, HP-

beta-CD seems to be a strong candidate, as it doesn’t

appear to elicit any IgE response. (GOULD, SCOTT

2005)

Alternatives to PEG as the main agent to different

allergic responses have also been proposed. While

compounds with a similar formulation are expected to

still cause allergic responses, neutral stabilizers such

as polyvinylpyrrolidone and its derivatives are a

possible alternative. It is often administered to large

numbers of individuals as a plasma expander to many

individuals with no reports of severe reactions

(BURNETT 2017).

Another factor to consider in COVID-19

vaccines, are potential changes in gene expression

arising from the Spike protein S, which is present in

some whole-protein vaccines or is the final

translational product of mRNA vaccines, which have

been recently described. (Evans 2021) These data are,

however, very preliminary.

Excluding pregnant women and adolescents, the

safety and effectiveness of these groups are unknown.

Other vaccines lack these two groups in the most

important phase III clinical trials. Clinical trials can

be supplemented in the future. It is mainly carried out

among healthy young men in the Middle East, while

the number of the elderly, women, and patients with

chronic diseases is limited.

As for efficacy, current vaccines seem to offer

protection against new variants, such as the high-

spreading Delta, and as such, their formulations are

most likely remaining unaltered for a while.

(GOV.UK 2021) In the trial of Heterologous

ChAdOx1 nCoV-19 and BNT162b2 prime-boost

vaccination elicits potent neutralizing antibody

responses and T cell reactivity, a total of 26

volunteers aged 25-46 years (median age 30.5 years)

received a dose of Oxford vaccine and then a dose of

Pfizer vaccine 8 weeks later. The variants selected

here are B.1.1.7 (Alpha, first discovered in the UK),

B.1.351 (Beta, first discovered in South Africa) and

B.1.617 (Delta, first discovered in India). (GROSS,

ZANONI, SEIDEL 2021) Studies have shown that

these variants are effectively neutralized by the sera

of all vaccinators.

It is important to note, that despite adverse effects

that are rare, COVID-19 vaccines are still considered

to be much safer than exposure to the virus, that even

for healthy people, might cause death or a variety of

lingering cardiac and neurologic symptoms

(NIKHRA 2021).

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