Abstract
At the beginning of the current pandemic, it was believed that severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection would
induce lifelong immunity and that reinfections would be unlikely.
However, after several cases of reinfection were documented in
previously infected patients, this was understood to be a false
assumption, and this waning humoral immunity has raised significant
concerns. Accordingly, long-term and durable vaccine-induced antibody
protection against infection have also become a challenge, as several
breakthroughs of COVID-19 infection have been identified in individuals
who were fully vaccinated. This review discusses the current evidence on
breakthrough COVID-19 infections occurring after vaccination.
Keywords: SARS-CoV-2, Breakthrough, Vaccination, COVID-19
Introduction
The emergence of severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) has resulted in many individuals becoming infected, more
than four million deaths, and has placed an unprecedented burden on
public health services worldwide (1-3). At the beginning of the
coronavirus 2019 (COVID-19) pandemic, it was speculated that SARS-CoV-2
infection would result in lifelong immunity, and reinfections would be
unlikely. However, there have been several documented cases of
reinfection in people previously infected with SARS-CoV-2 (4).
Therefore, waning humoral immunity is increasingly recognized as a
significant concern. Accordingly, long-term and durable vaccine-induced
antibody protection against infection is now a significant challenge
facing scientists (5). Since the SARS-CoV-2 vaccination program started,
several breakthroughs of COVID-19 infection have been identified in
individuals who had been vaccinated (6). In this article, we review the
literature on breakthrough SARS-CoV-2 infections following vaccination.
Persistence of natural- or vaccine-induced antibodies
Miscellaneous reports are available about the duration of immunity
persistence in COVID-19-infected patients. Several studies have
concluded that anti-SARS-CoV-2 antibodies decline rapidly, lasting up to
three months after the primary infection (7), while others report
post-infection antibody persistence for up to five months (8). Some
studies have shown that the mRNA vaccines, Moderna and Pfizer, have an
efficacy of up to 95% for preventing symptomatic SARS-CoV-2 infection
7-14 days after the second dose (9, 10). However, it should be noted
that mild antibody decreases, following natural- or vaccine-induced
immunity does not necessarily indicate an absolute waning of immunity,
as, in most people, a durable immunity against secondary COVID-19
disease would be possible up to 8-months following infection or
vaccination through anti-S memory B cells (11).
Definition of breakthrough infections
Breakthrough infections can be defined as the reinfection with a
pathogen after being fully vaccinated for the same disease. This
phenomenon has been well documented following many viral and bacterial
vaccines, and SARS-CoV-2 infection has not been an exception (12-14).
However, another related phenomenon is vaccine-associated enhanced
diseases (VAED), which is not the focus of the present review. This term
points to the situation in which an individual who received a vaccine
develops a more severe or modified presentation of that infection when
later exposed to that pathogen than when infection occurs with no prior
vaccination history (15).
Underlying causes and characteristics of SARS-CoV-2
infections, following vaccination
As previously mentioned, waning immunity after a de novo infection or
vaccination can be the reason that some people get infected or
reinfected following COVID-19 vaccines (16-18). Moreover, some
individuals with diminished capacity to produce protective antibodies,
such as immunosuppressed patients, are also susceptible to being
infected even after being naturally infected with this virus or
receiving both vaccine doses (19-21). Ineffective antibody production,
due to relatively ineffective vaccines, an inadequate number of doses,
and the time after the vaccination are also involved in the pathogenesis
of post-vaccination infections (22). It is not unusual to get infected
in the first 14 days following the first dose of the vaccine since
protective immunity cannot build within this period (23, 24). For
example, it has been estimated that the Pfizer COVID-19 vaccine has
efficacy in preventing COVID-19 infection of 52.4% before and 90.5%
one week after the second dose, respectively (25). Therefore, vaccinated
people may develop an infection before the booster shot takes full
effect.
Furthermore, the effectiveness of anti-SARS-CoV-2 vaccinations in
preventing infection from the new variants is still unclear. In general,
vaccinated individuals are less likely to get infected than those who
are unvaccinated, although the level of prevention strongly depends on
the specific variant of concern (VOC) (26). The evolution of mutations
in the genes of SARS-CoV-2 can affect the efficacy of vaccine- or
natural-induced immunity (27). The emergence of new SARS-CoV-2 variants,
including the alpha (B.1.351) or delta (B.1.617.2) variants, with higher
transmissibility and less susceptibility to the previously produced
protective antibodies, is another reason why some individuals become
infected even after being fully vaccinated (27, 28). Thus, these
variants could be the reason why vaccine breakthrough infections occur
two weeks post-vaccination, even with high titers of vaccine-induced
antibodies (29). However, some new variants are less likely to escape
vaccine-induced immunity and, therefore, less problematic (30). Although
most cases of post-vaccination infections are because of VOCs (31), it
does not appear that these cases are due to remarkable genetic diversity
or spike protein mutations in VOCs (32).
Researchers have found that vaccination with the ChAdOx1 or BNT162b2
vaccines can significantly decrease new positive SARS-CoV-2 reverse
transcriptase-polymerase chain reaction (RT-PCR) from 21 days after the
first dose onwards, with greater immunity following a second dose and
significant reductions for symptomatic infections and infections with
higher viral loads (cycle threshold, Ct < 30) (27, 33).
However, breakthrough infections with lower viral loads can further
reduce onward transmission (34). Nevertheless, there is some concern
that the new variants which evade vaccine-induced immunity may also lead
to asymptomatic infection, resulting in more viral spread (35).
Moreover, since the COVID-19 vaccine is administered by injection and
designed to prevent viremia, they are thought to be unable to prevent
nasal SARS-CoV-2 infection, resulting in more asymptomatic shedding and
more viral spread through asymptomatic patients’ upper airways (36).
However, it is thought that those vaccinated against COVID-19 would have
less severe and shorter breakthrough infections with lower viral loads
(37). Studies have shown that post-vaccination COVID-19 infections less
commonly require hospitalization and admission to an intensive care unit
(ICU) than infections occurring in non-vaccinated individuals (38). The
risk factors of SARS-CoV-2 infection after COVID-19 vaccination have
been reported to include younger age, adverse health determinants, such
as extended social isolation, obesity, unhealthy lifestyle, less
adherence to preventive measures, and the presence of concomitant
comorbidities, including renal disease, and receiving immunosuppressant
medication (39).
Prediction of antibody response to vaccination
A clinical response to a vaccine booster can be predicted by developing
symptoms, such as those generally associated with the flu shortly after
vaccination. This can also be confirmed through the identification of
high titers of neutralizing antibodies (40). Following vaccination and
same-day testing, active daily symptoms can help evaluate or predict
protective immune response following SARS-CoV-2 vaccination (41).
Differentiate between pre-and post-vaccination infections
Another interesting issue is that many vaccinated individuals have
received the vaccine within the SARS-CoV-2 incubation period and might
have received their RT-PCR results after being vaccinated. Some
individuals even had the prodromal manifestations of COVID-19, such as
rhinorrhea or headache, which they neglected or misunderstood as a
simple allergy or migraine. However, usually, vaccine recipients get
infected after vaccination, in the first 14 days following vaccination,
before the antibodies have had time to develop and produce effective
protective immunity (42), making it challenging to identify the exact
date of infection as being pre- or post-vaccination. Nonetheless, the
dates of symptom onset, in addition to the usual incubation period, can
be used to estimate the time of exposure (43). Another beneficial tool
to differentiate post-vaccination breakthrough infections from
infections acquired just before vaccination can be evaluating the Ct, so
patients with a Ct < 30 are more likely to have been infected
after vaccination than those with higher values (44).
The difference between various vaccines in preventing
breakthrough infections
At the time of writing, no studies have been published on the efficacy
of various anti-SARS-CoV-2 vaccines and any differences in preventing
breakthrough COVID-19 infections. However, it can be inferred that this
phenomenon would be more likely after being vaccinated with vaccines
that have lower efficacy and potency (45).
Differentiating between COVID-19 infection symptoms and
vaccine side effects
Several manifestations of SARS-CoV-2 infection are similar to
vaccine-induced side effects. Symptoms, such as a sore throat, myalgia,
headache, fever, chills, cough, rhinorrhea, diarrhea, and nausea, can be
presented both as an adverse reaction after vaccination and a result of
breakthrough SARS-CoV-2 infection. Thus, these symptoms do not help to
distinguish between these two conditions (46). Nevertheless, shortness
of breath and chest pain/tightness is less likely to occur following
COVID-19 vaccination unless it results from vaccine-induced pulmonary
thromboembolism (47) or it is an exacerbation of a pre-existing
condition. In addition, anosmia and persistent cough are specific
manifestations of a COVID-19 infection, rather than being side effects
of vaccination. Furthermore, vaccination side effects tend to last for a
short period, usually disappearing within a few days. The persistence of
symptoms several days after vaccination should prompt testing for
SARS-CoV-2 infection. Moreover, a history of close contact with a
confirmed or suspected case of COVID-19 can also be a useful criterion
in considering a probable infection, which necessitates confirmation via
diagnostic laboratory or imaging tools.
Strategies to prevent and decrease post-vaccination
breakthrough infections
Due to the documented waning immunity following the complete vaccine
dosing schedule, booster doses may be necessary at periodic intervals
after the second vaccine dose to maintain adequate immunity (48).
Perhaps, vaccines being administered via the mucosal route would be an
advantageous option to be studied and produced since they may induce
higher levels of local protective immunity and lead to the settlement of
T and B cells in the nasopharyngeal tissue (49). From a public policy
perspective, further public education around the need for vaccination is
required. People remain hesitant to vaccinate, with some media outlets
reporting nihilism following the latest delta strain and breakthrough
infections with anecdotal stories rapidly spreading unhelpful messages
against vaccination (50). Hesitancy even remains among highly educated
and high-risk individuals such as medical students (51), healthcare
workers (52), and people with autoimmune disorders (53). Understanding
why this is the case and addressing these factors needs to be a public
health priority supported through dedicated resources and rapid
information sharing to disseminate recommendations across countries.
Some research and evaluation are already underway for the broad topic of
vaccination hesitancy (54, 55). However, the impact of breakthrough
infections and how this relates to the uptake of vaccinations is
unknown.
Conclusion
All the issues mentioned above reinforce the fact that vaccination does
not entirely prevent SARS-CoV-2 infections but will lead to less
morbidity and mortality, as demonstrated by less hospitalization and
less need for ICU care. In addition, the reality that vaccinated
individuals may develop asymptomatic breakthrough infections should be a
concerning issue, as this increases the risk of viral transmission and
spread in the community. Moreover, the relatively high rates of
post-vaccination infection, either due to insufficient efficacy of the
vaccines or through the evolution of new variants, highlight the
importance of maintaining social distancing and other preventive
measures, even when vaccinated.