Since the outbreak of COVID-19 infection in late 2019 in China, it has spread globally causing massive morbidity and mortality. It spreads through contact, droplets, and aerosol transmission (PriyankaChoudhary et al., 2020). The morbidity and mortality rates in developed countries slowed down because COVID-19 vaccines provided immune protection against SARS-CoV-2 (Arbel et al., 2021; Yan et al., 2021a). In spite of the high efficacy and safety profile of vaccines as reported in various studies, some patient groups are still undecided whether to receive vaccinations (Abu-Farha et al., 2021; Yigit et al., 2021a; Choudhary et al., 2021; Zhou et al., 2021). Previous studies and guidelines have documented the special considerations for different clinical special populations, and medical staff should assist in the risk–benefit analysis to make a proper clinical decision (Yan et al., 2021b; Furer et al., 2021; Powers et al., 2021; Soiza et al., 2021).

Worldwide, a significant portion of people in developed countries has completed COVID-19 vaccination schedule, while some in developing and under-developed countries have not completed basic vaccination schedules due to resources scarcity and income disparity (The Lancet Infectious Diseases, 2021; Van De Pas et al., 2022). Vaccination does not confer sufficient lifelong protection: post-vaccination humoral responses decrease after 3–6 months (Chemaitelly et al., 2021; Levin et al., 2021; Erice et al., 2022). Early studies on booster vaccination show that the infection rate in the booster cohort is lower compared with those without receiving a booster (Bar-On et al., 2021). Of even greater concern, vaccine efficacy dwindles when it comes to Delta- and Omicron-related variant infections, which is associated with higher viral load and transmissibility (Campbell et al., 2021; Torjesen, 2021). Patients without sufficient protective efficacy run a higher risk of symptomatic infection, severe hospitalization, mortality, and long COVID-19 syndrome (Yan et al., 2021c).

This prompts a key question: who should receive a booster 6 months after the last dose since vaccination per se may be associated with risks? This paper evaluates the risk and benefits of booster vaccination to assist clinical decision making. Literature data were retrieved from electronic databases (PubMed, Medline, Scopus, Cochrane, Google Scholar) on December 14, 2021, with the following keywords: COVID-19, Vaccine, Booster, and Variants. Related articles are reviewed to address the key question.

Waning humoral responses have been reported worldwide 6 months after completion of vaccination (one to three doses, depending on vaccination design) (Levin et al., 2021; Chemaitelly et al., 2021; Shrotri et al., 2021). This is particularly evident in men, participants older than 65 years old, or people with immunosuppression (Levin et al., 2021) for BNT162b2 (Pfizer-BioNTech) recipients. In spite of the waning antibody titer after 6 months of completion of BNT162b2 (Pfizer-BioNTech) vaccination, the protection against hospitalization and death persists at a robust level. The estimated effectiveness of BNT162b2 (Pfizer-BioNTech) against SARs-CoV-2 infection peaked at 77.5% (95% CI, 76.4–78.6) in the first month after the second dose, but it progressively dropped to 20% 5 months after the second dose (Chemaitelly et al., 2021). Thus, reinfection by SARS-CoV-2 is possible (Cromer et al., 2021). Vaccine protection against major variants of SARS-CoV-2 is summarized in Tables 2–8. One of the major concerns is that all vaccines express the ancestral SARS-CoV-2 spike protein, whereas currently circulating variants such as Delta variant possess several mutations to evade the response, resulting in a 4-fold lower neutralizing antibody response to Delta-variant infections (Kent and Juno, 2021).

A booster vaccination is not without risks. Myocarditis has been reported worldwide, particularly in young male recipients after receiving the second dosage of BNT162b2 (Pfizer-Biotech) vaccine (Mevorach et al., 2021). The risk ratio 30 days after the second dose in fully vaccinated recipients (without booster) is 2.35 (95% CI, 1.10–5.02), while the risk ratio rises to 8.96 (95% CI, 4.50–17.83) in male subjects between 16 and 19 years old. It is uncertain whether the third dose will trigger further myocardial damage. However, severe complications such as myocarditis or allergy from the first two doses of BNT162b2 are relatively rare (Barda et al., 2021). Guillain–Barre syndrome has also been reported in adenovirus-vectored COVID-19 vaccines (WHO, 2021b). For the majority of fully vaccinated recipients who have no significant associated complications, a booster vaccination may be safer.

The booster may greatly safeguard the effect offered by the first two dosages. When serum antibody titer drops below the protective threshold, a “start over” vaccination may still be necessary, which may also trigger complications. Studies also reveal that antibody levels in the aged population are relatively lower after full vaccination, though no severe complications are observed (Wei et al., 2021). Therefore, a booster vaccination may be necessary for this population.

Overall, vaccination is very safe, though common transient side effects happen, and a booster is a good option that significantly consolidates the protective effect to fight against this long-term pandemic. It is recommended that the earliest time to receive a booster is 6 months after the initial vaccination (Chemaitelly et al., 2021; Levin et al., 2021). A future study evaluating long-term serum antibody titer and booster clinical trials are needed for guidance on booster vaccination.

Though booster vaccination is associated with both benefits and risks, overall it is safe and effective. The BNT162b2 third-dose booster vaccination in Israel showed that the side effects were mild and self-limiting, including immunocompromised patients and senior citizens (Shapiro Ben David et al., 2021). The most common side effects were fatigue (19.6%), myalgia (9.2%), and fever (8.1%) in immunocompromised patients and fatigue (21.3%), myalgia (9.9%), and fever (9.2%) in senior citizens. Over two-thirds of the recipients developed a better or similar response compared to the second dose. This is consistent with the study in the United Kingdom which showed that although there were numerous local or systemic side effects in the short term, the vaccine efficacy exceeded 60% within 2–3 weeks (Menni et al., 2021).

One concern of advocating booster vaccination is related to equity (The Lancet Infectious Diseases, 2021). The income disparity between developed countries and developing countries results in a competition for gaining access to vaccinations. Up to August 9, 2021, over 80% of the vaccines were distributed to high-income countries, while only 20% were in low-income countries with only 3% of the African population fully vaccinated (without a booster) (Kherabi et al., 2021; The Lancet Infectious Diseases, 2021). This results in increasing reporting of variants in different countries, in particular from low-income countries (see Supplementary Appendix with reports of different variants reported internationally). Vaccines thus should be made available to other countries before offering domestic booster vaccinations to reduce variants transmission and new variants from evolving (Dyer, 2021; Schaefer et al., 2021).

The vaccination schedule should be individualized for different populations, such as healthy individuals without previous SARS-CoV-2 infection and COVID-19 survivors with prior SARS-CoV-2 infection. The underlying reason is related to the waning trajectory of antibody titers in different populations. After a two-dose schedule of mRNA-based vaccination, healthy subjects developed similar antibody levels to COVID-19 survivors who recover from the infection for 1 year and receive single-dose mRNA-based vaccination (Gluck et al., 2021). None of the study participants experienced reinfection. The half-life of anti-SARS-CoV-2 IgG antibody ranges between 85 and 158 days (Lumley et al., 2021; Dan et al., 2021; den Hartog et al., 2021), while some studies also show the immunity may last over 300 days (Gluck et al., 2021; Lee et al., 2021). There is uncertainty about the booster schedule for different populations, and this may create a burden on healthcare service and spark controversy on vaccine equity between developing countries and developed countries (The Lancet Infectious Diseases, 2021). Overall, vaccine boosters quickly increase antibody levels since the large number of memory B cells and plasma cells derived from previous immunity drives rapid antibody productions after booster vaccination (Ebinger et al., 2021; Gobbi et al., 2021; Liao et al., 2021; Turner et al., 2021). Booster vaccination thus is protective against SARS-CoV-2 infection, but the booster schedule requires further studies.

Though vaccine recipients may have more persistent nasopharynx-homing SARS-CoV-2-specific T cells compared to infection-naïve subjects (Neidleman et al., 2021), a further booster vaccination still induces a stronger immune response while giving manageable side effects (Ebinger et al., 2021).

The US Center for disease Control and Prevention and French National Authority of Health have recommended prioritization of booster vaccination for high-risk groups, subjects aged over 65 years, subjects between 50 and 64 years with underlying medical conditions, healthcare workers, and residents of long-term care facilities (Burki, 2021; Kherabi et al., 2021). The United Kingdom is currently considering a third-shot booster vaccination for all adults (Burki, 2021).

Healthcare workers are at high risk of infection. The British study of BNT162b2 vaccine showed vaccine effectiveness of 70% (95% CI 55–85) 21 days after the first dose and 85% (95% CI 74–96) 7 days after two doses in healthcare staff when the dominant variant was Alpha (B.1.1.7) (Hall et al., 2021).

The timing to receive booster vaccination is subject to debate. A study focusing on the immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) recommends a 3-month interval to receive a booster since a high protective efficacy is maintained until 3 months (Voysey et al., 2021). Efficacy was higher with a 12-week prime–boost interval (vaccine efficacy 81.3%, 95% CI 60.3–91.2), compared with a 6-week interval (vaccine efficacy 55.1%, 95% CI 33.0–69.9). Meanwhile, BNT162b2 (Pfizer) vaccine recommends a 6-month interval to receive a booster (CDC, 2021a).

Whether subjects with previous SARS-CoV-2 should receive a three-dose vaccination schedule and when they should receive the booster vaccination as antibody titers drop are still under debate. The antibody responses to the first vaccine dose in individuals with pre-existing immunity are equal to or exceed the titers found in naïve individuals after the second dose of BNT162b2 (Pfizer-BioNTech). The antibody titers against VOC, Delta variant (1.617.2), in COVID-19 recoverers (at least 11 months after complete resolution of the previous infection) receiving one-dose ChAdOx1 nCoV-19 vaccine are similar to or higher than the counterparts receiving two-dose BNT162b2 (Pfizer-BioNTech) (Havervall et al., 2021). BBV152 (Bharat Biotech) vaccine of India also induces a similar response in COVID-19 recoverers, suggesting one-dose vaccinations can give similar antibody levels as two-dose vaccinations (Kumar et al., 2021). Their adverse reaction to vaccination is higher than those of healthy adults (Krammer et al., 2021). COVID-19 recoverers receiving a second-dose vaccination show no additional benefits since they have reached the peak of their immunity after the first dose (Lozano-Ojalvo et al., 2021). These studies suggest that one-dose vaccinations in COVID-19 recoverers is sufficient to confer protection non-inferior to healthy individuals with two-dose vaccinations (Cavalcanti et al., 2021; Vicenti et al., 2021), and they should be put lower on the vaccination priority list (Saadat et al., 2021). Despite the similar efficacy, the post-vaccine symptoms are more prominent for those with prior infection after the first dose (Ebinger et al., 2021).

The absolute and relative contraindications of vaccination are documented in Tables 9 and 10. Absolute contraindications include mainly severe allergic reactions to its constituents shown in Table 9 (USCDC, 2021a). Relative contraindications and recommended actions are listed in Table 10. Subjects with relative contraindications are recommended to discuss individual risk profiles to plan their vaccination decision. Counseling should include risk factors, relative contraindications, benefits and risks of vaccinations, alternative vaccines, and risks of without vaccinations. Table 11 documents the ingredients of 24 COVID-19 vaccines with emergency use authorizations by national regulatory authorities (as of October 26, 2021).

Heterologous vaccination (Com-COV study) is safe and induces robust immunity without serious adverse events (Borobia et al., 2021; Liu et al., 2021c; Moghnieh et al., 2021). This has been performed in subjects receiving “BNT162b2 (Pfizer/BioNTech) plus ChAdOx1 nCoV-19 (AZD1222)” and “BNT162b2 (Pfizer/BioNTech) plus BBIBP-Cor-V (Sinopharm).” The interim analysis documents that heterologous ChAdOx/BNT immunization regimen with 10–12 weeks vaccination interval is well tolerated and slightly more immunogenic compared to homologous BNT/BNT vaccination with 3-week intervals. A recent randomized controlled trial showed that heterologous vaccination with other vaccines after the initial two doses (either two-dose ChAdOx-1 or BioNTech) yields a higher SARS-CoV-2 anti-spike IgG titer and stronger cellular response (Munro et al., 2021). This may be a viable choice for countries without a stable source of vaccines or in immunocompromised patients who could not produce sufficient protective antibodies (Borobia et al., 2021; Liu et al., 2021c; Hillus et al., 2021; Moghnieh et al., 2021). Initial SARS-CoV-2 vaccination response can predict booster response; thus, reassessment of antibody response may be a viable choice whether to receive homologous or heterologous vaccination (Perkmann et al., 2021).

Timing of vaccinations is vital in certain patients after specific treatments. Suboptimal immunological response has been found in patients receiving BNT162b2 (Pfizer-BioNTech) after rituximab administration (Kant and Geetha, 2021). Delaying vaccination for 6 months after rituximab administration or B-cell reconstitution has been suggested in previous studies (Kant et al., 2021). Vaccine booster schedule should be individualized according to the half-life of immunity decline. A British study shows that an extended interval before the second dose of ChAdOx1 nCoV-19 leads to increased antibody titers, while a third dose of ChAdOx1 nCoV-19 induces antibody that correlates with higher efficacy after second dose due to robust T-cell responses (Flaxman et al., 2021).

Patients receiving immunosuppressants or with chronic kidney impairment receiving renal replacement therapy also have suboptimal anti-SARS-CoV-2 antibodies after the second dose (Boyarsky et al., 2021a; Boyarsky et al., 2021b; Bensouna et al., 2021; Kamar et al., 2021; Peled et al., 2021; Werbel et al., 2021). A booster dose of mRNA-1273 vaccine induces serological response in 49% of renal recipients who are refractory to produce antibodies after two doses (Benotmane et al., 2021). This is similar in patients receiving solid organ transplants on immunosuppressants and with negative antibody titers before the third dose: 25% of them develop high-positive antibodies after a third dose, while over two-thirds of them remain negative (Werbel et al., 2021). A significant proportion of patients who fail to develop immunity after a third-dose booster is on triple immunosuppressants (Benotmane et al., 2021). The SENCOVAC study shows that an absence of antibody protection is associated with kidney transplant recipients due to their immunosuppression therapy (odds ratio 20.56, p < 0.01), while receiving BNT162b2 increases the chance of antibody response (odds ratio 6.03, p = 0.02) (Quiroga et al., 2021). These patients are advised to adopt persistent isolation measures and consider booster vaccines to optimize protection against COVID-19 infection (Quiroga et al., 2021). Use of rituximab is common in cancer or autoimmune disease treatments leading to failure of immunological response (Yahav et al., 2021). Heterologous vaccination leads to stronger induction of antibodies and CD4 T cells in immunocompromised patients: SARS-CoV-2-specific antibodies and T-cells response after second vaccination were induced 100% and 70.6% in transplant recipients (Baker et al., 2021; Schmidt et al., 2021).

A recent systematic review compared the relative likelihood of non-responders (Galmiche et al., 2021). The proportion of non-responders is higher among solid organ transplant recipients (range 18–100%), hematological malignancy (range 14–61%), cancers (2–36%), and dialysis usage (2–30%). Risk factors of failure of antibody induction include older age, use of corticosteroids, immunosuppressants, and anti-CD20 agents.

Currently, a new approach is consideration of immunosuppressant dosage adjustment or additional booster to maximize immunological response induction (Albach et al., 2021; Yan et al., 2021b; Connolly et al., 2021; Mackintosh et al., 2021; Yahav et al., 2021). With vaccination-refractory in immunocompromised subjects (solid organ transplant recipients) (Chavarot et al., 2021), recommendation of an additional dose is encouraged since a third vaccine dose increases the seropositivity prevalence from 40% to 68% (Husain and Argyropoulos, 2021). The seropositivity is protective against symptomatic infection, while it is unlikely to carry a significant risk of adverse events (Husain and Argyropoulos, 2021).

Cancer patients benefit from third-dose vaccinations since they run a high risk of failed induction of immune memory (Peeters et al., 2021). The CANVAX Cohort Study shows that immune responses to SARS-CoV-2 vaccines are moderately impaired in patients with cancer, while antibody testing may be effective to identify immune-inert patients to receive booster vaccinations (Naranbhai et al., 2021). A third-dose BNT162b2 (Pfizer/BioNTech) vaccination demonstrated a median 3-fold increase of neutralizing antibody response with mild adverse events (Shroff et al., 2021). This should be similarly considered in cancer patients with active anti-neoplastic treatment (Peeters et al., 2021). In view of the breakthrough infections with multiple lineages of variants, immunocompromised patients are at risk of severe diseases (Deng et al., 2021; D'Amelio et al., 2021). In terms of safety, immunocompromised patients are not at an increased risk of vaccine-related adverse events (Mackintosh et al., 2021).

Breakthrough infections have been reported worldwide. Breakthrough infections are mild in healthy adults (Abbasi, 2021). Thus, management of breakthrough infections should include a thorough clinical history review to determine the presence of risk factors and appropriate actions (Figure 1).

Common reasons related to this include: 1) infection of variant strains (Bosch et al., 2021); 2) low circulating antibody levels as time elapsed from the previous second dose (Chemaitelly et al., 2021; Levin et al., 2021); 3) insufficient induction of antibody due to multiple comorbidities or immunocompromised state (Albach et al., 2021; Arya et al., 2021); 4) history of substance abuse (Wang et al., 2022); and 5) old age (Butt et al., 2021; Glatman-Freedman et al., 2021).

Within 6 months after the last dose of mRNA-based vaccination, the antibody is still protective against COVID-19 disease (El Sahly et al., 2021; Thomas et al., 2021). Consideration of vaccine-resistant variant strain infection should be the top priority. Low serum antibody level leading to insufficient protective efficacy is the common reason for breakthrough infections. Booster vaccination after 6 months, regardless of antibody level, should be considered (Ebinger et al., 2021; Gobbi et al., 2021; Liao et al., 2021; Turner et al., 2021), though there is evidence suggesting breakthrough infections do not necessarily correlate with lack of vaccine-induced immunity (Duarte et al., 2021).

Patients with multiple comorbidities leading to the immunocompromised state should consider booster vaccination, with either homologous or heterologous vaccines (Baker et al., 2021; Schmidt et al., 2021). The multiple comorbidities include solid organ transplant patients on immunosuppressants (Werbel et al., 2021), autoimmune diseases with failed induction of antibody despite full-dose vaccination schedule (Yahav et al., 2021), chronic kidney disease with renal replacement therapy (Boyarsky et al., 2021a; Boyarsky et al., 2021b; Bensouna et al., 2021; Kamar et al., 2021; Peled et al., 2021; Werbel et al., 2021), poorly controlled hypertension, diabetes mellitus (Brosh-Nissimov et al., 2021), and cancers (Peeters et al., 2021).

This paper provides an updated evaluation of booster vaccination: its necessity, concerns, and benefits on variant strains. It gives a detailed description of the efficacy and safety of vaccination on variant strains. However, there are limited data on the effect of booster vaccination on Omicron strains at the time of writing, and Omicron-strain vaccination has been under development by vaccine manufacturers; thus, clinical trials of newly modified vaccines have not started. Booster vaccination brings benefits to the waning immunity and protective efficacy of COVID-19 vaccines. Booster vaccination induces immunological memory by elevating circulating anti-SARS-CoV-2 antibody level. Its associated risk is manageable, while risk–benefit analysis should be evaluated by medical health staff to manage comorbidities and rule out contraindications for vaccinations. Special populations should have an alternative vaccination schedule to boost their protective antibodies against multiple lineages of SARS-CoV-2 variants. These patients are not at a higher risk of vaccine-associated adverse events. More research is required on the schedule of booster vaccination and the type of booster vaccine for special populations.

1) Not in contravention of the European Respiratory Society (ERS) policy on tobacco