key: cord-0946525-chzamfb2
authors: Notarte, Kin Israel; Guerrero‐Arguero, Israel; Velasco, Jacqueline Veronica; Ver, Abbygail Therese; Santos de Oliveira, Maria Helena; Catahay, Jesus Alfonso; Khan, Md. Siddiqur Rahman; Pastrana, Adriel; Juszczyk, Grzegorz; Torrelles, Jordi B.; Lippi, Giuseppe; Martinez‐Sobrido, Luis; Henry, Brandon Michael
title: Characterization of the significant decline in humoral immune response six months post‐SARS‐CoV‐2 mRNA vaccination: A systematic review
date: 2022-03-09
journal: J Med Virol
DOI: 10.1002/jmv.27688
sha: bb2decbb002a37cf807167bb8553f993d7cf9f0e
doc_id: 946525
cord_uid: chzamfb2

Accumulating evidence shows a progressive decline in the efficacy of coronavirus disease 2019 (COVID‐19) (severe acute respiratory syndrome coronavirus 2 [SARS‐CoV‐2]) messenger RNA (mRNA) vaccines such as Pfizer‐BioNTech (mRNA BNT161b2) and Moderna (mRNA‐1273) in preventing breakthrough infections due to diminishing humoral immunity over time. Thus, this review characterizes the kinetics of anti‐SARS‐CoV‐2 antibodies after the second dose of a primary cycle of COVID‐19 mRNA vaccination. A systematic search of the literature was performed and a total of 18 articles (N = 15 980 participants) were identified and reviewed. The percent difference of means of reported antibody titers was then calculated to determine the decline in humoral response after the peak levels postvaccination. Findings revealed that the peak humoral response was reached at 21–28 days after the second dose, after which serum levels progressively diminished at 4–6‐month postvaccination. Additionally, results showed that regardless of age, sex, serostatus, and presence of comorbidities, longitudinal data reporting antibody measurement exhibited a decline of both anti‐receptor binding domain immunoglobulin G (IgG) and anti‐spike IgG, ranging from 94% to 95% at 90–180 days and 55%–85% at 140–160 days, respectively, after the peak antibody response. This suggests that the rate of antibody decline may be independent of patient‐related factors and peak antibody titers but mainly a function of time and antibody class/molecular target. Hence, this study highlights the necessity of more efficient vaccination strategies to provide booster administration in attenuating the effects of waning immunity, especially in the appearance of new variants of concerns.

The coronavirus disease 2019 (COVID-19) pandemic claimed millions of lives worldwide and remains an unprecedented challenge to global public health. 1, 2 Despite the increasing availability of therapeutics against severe acute respiratory syndrome coronavirus 2 (SARS- infection, mass vaccination is the mainstay for limiting new infections, reinfections, breakthrough infections, and unwanted sequelae from COVID-19. [3] [4] [5] [6] Although nationwide immunization programs have already been implemented in most countries, the mass production, allocation, and accessibility to COVID-19 vaccines remain a hurdle, especially in low-income countries where administration of primary and adjunctive doses could be challenging. 7 Among different types of COVID-19 vaccines, the utilization of messenger RNA (mRNA)-based vaccines is unprecedented. 8 Despite the efficacy of mRNA vaccines in reducing the risk of developing severe COVID-19 illness, ample evidence showed the progressive decline in their efficacy for preventing SARS-CoV-2 infections. 9 Such vulnerability is correlated to the significant decline in anti-SARS-CoV-2 antibodies (Abs) over time. [10] [11] [12] This waning humoral response could lead to breakthrough infections, thus highlighting the potential role of serologic testing to assess vaccine immunogenicity and protective efficacy. Although the role of T cells and B memory cells from vaccine-induced immunity has yet to be fully elucidated, multiple studies showed that Ab levels directly correlate with the risk of vaccine reinfection and breakthrough, with low levels of anti-SARS-CoV-2 immunoglobulin G (IgG) in patients with infections correlating with high viral load and duration of viral shedding. 3, 4 In addition, the emergence of the new SARS-CoV-2 Omicron variant (B.1.1.529), with potential for high immune escape, highlights the necessity for vaccine boosters and high Ab titers for an improved immunoprotection. 13 Thus, to better understand the rate of decay of anti-SARS-CoV-2 Abs through time, this rapid systematic review was designed to analyze humoral response within a 6-month period among recipients of the Pfizer-BioNTech or Moderna COVID-19 mRNA-based vaccines to provide further evidence on the necessity of boosting vulnerable populations. the former because it is now increasingly clear that IgM plays a minor role against COVID-19, as it has lower sensitivity (64%), specificity (99%), and accuracy (94%) compared to IgG (93%, 100%, and 98%, respectively). 14 IgM antibodies were also found to decline early (i.e., at Day 20 postvaccination) and have lower neutralizing potential. 15 The latter because we only focused on humoral immunity due to limited data and lack of standardization of available cellmediated immunity assays, hence imposing difficulty in data analysis.

Data were extracted independently from each article by two authors into a spreadsheet. A third author checked the extracted data for completeness and accuracy. Any disagreements were resolved by consensus among the authors.

Descriptive and outcome data were extracted from the included studies, including the type of vaccine, country of origin, sample size, age range or median age of the population, type of serologic test employed and its manufacturing company, analyzer used, immunoglobulin measured, and molecular target of immunoglobulin.

In addition, serial or nonserial serologic measurement determination was done, to differentiate which study performed better patient follow-up, thus reducing methodologic bias due to greater accountability for interindividual variability despite generally lower sample size for serial serologic sampling. Additional data were requested from the original study authors when necessary.

All data reported in this study were in reference to the peak humoral response after a primary vaccination cycle with two doses. However, due to significant heterogeneity in the assays used to probe antibody titers, the antibody measurements reported in the articles were standardized using the percent difference of means. This shows the absolute value of the ratio of the difference between two groups, (groups A and B which pertain to antibody titer measurements on the peak and after the peak of humoral response) and their average, expressed as a percentage to enable standard comparison of these data regardless of their units of measurements and the diagnostic tools used for their quantification. It is computed using the formula below:

Difference of Means

Group A-Antibody titer on the peak humoral response; Group B-Antibody titer after the peak humoral response

Therefore, values are reported as a percentual decrease from the peak. Time points were also standardized to represent the number of days after the second vaccine dose.

The demographic parameters used in this study were limited to age, reporting longitudinal data on Ab measures, an observed decline from peak levels of anti-RBD IgG ranged from 94% to 95% at 90-180 days post peak, while the anti-spike IgG showed a decline that ranged from 55% to 85% at 140-160 days after the peak ( Figure 2 ). With respect to the vaccine brand, Pfizer-BioNTech displayed a 90%-94% decline of anti-RBD IgG at 150-161 days following the peak and a decline of IgG anti-spike protein ranging from 55% to 95% at 140-180 days after the peak. Meanwhile, Moderna exhibited a 69%-96% decrease in anti-RBD IgG at 150-174 days from the peak, and a 45% decline in antis-pike IgG 90 days posttiter peak.

A consistent decrease in humoral immunity postvaccination was found across all age groups ranging from 53% to 96% ( Figure 3 ).

Similarly, a consistent decline in Ab titers regardless of sex was also noted. Females reported a 91%-93% decrease in their anti-RBD IgG levels, similar to males (ranging from 89% to 92%) ( Figure 4 ).

Anti-spike IgG levels in females decreased by 83%, also close to the decline seen in males (84%) (Figure 4 ). Regardless of serostatus, a diminished humoral immunity post-mRNA vaccination was evident.

However, the Ab titers post second dose of mRNA vaccine displayed varying trends ( Figure 5 ). One study showed a 90% decrease of titers in the seronegative group, which is higher than the decline observed in the seropositive group (79%) ( Figure 5 ). This is in contrast with two studies, one showing a 52% and the other a 60% decline in their seronegative participants, which is lower than the observed decline in their seropositive participants (68% and 74%, respectively) ( Figure 5 ).

For comorbidities cohorts, there was a consistent decrease in the total antibody and IgG levels among those individuals with kidney disease and undergoing hemodialysis (93%), heart disease and hypertension (91%), diabetes mellitus (90%), and immunologic disorders (85%).

Although most of the studies focused on IgG titers, one study measured the levels of anti-spike IgA with a decline up to 72% at 150 days after its peak, consistent with the rate of decay of other immunoglobulins. Conversely, a study from Italy reported the decline in total Ig reaching only up to 56% at 150-day post peak, which is lower than the rate of decline measured in other studies. There is 87% decrease 90 days after the peak rise of total antibody titer on Days 0-29 after full vaccination

There is 89% decrease 120 days after the peak rise of total antibody titer on Days 0-29 after full vaccination

There is 92% decrease 150 days after the peak rise of total antibody titer on Days 0-29 after full vaccination

There is 95% decrease 180 days after the peak rise of total antibody titer on Days 0-29 after full vaccination Kertes et al. 23 Pfizer-BioNTech Studies looking into the relationship of age and humoral response after undergoing Pfizer-BioNTech vaccination noted an inverse relationship on the antibody titers mounted. 12, 35 The studies included in Table 2 highlighted a similar trend. Regardless of the age group, there was a decline of titers starting 1 month after the second dose of vaccination ( Figure 3 ). The mounted antibody titers are initially higher in the age group <60 years, but the rate of decline was consistent across all age groups. These all suggest the need for a booster vaccine dose for all age groups, but in low resource settings, prioritization should be given to older age groups who mount weaker humoral responses and overall lower antibody titers.

Ab titers of females were higher even after a humoral decline in all studies (Table 3) ; however, the percentage decline from the peak was similar for both sexes (Figure 4) . 12, 23 Although it is important to note that overall Ab titers may be influenced by the larger female population cohort (6238 females vs. 3128 males) involved in the included studies, this might be attributed to the sex-based difference in humoral immunity which affects vaccine responses.

Previous studies indicated that females have a greater humoral response attributed to hormonal differences and X chromosomes leading to biallelic expression of certain genes. 36 Several studies support this given the higher Ab titers mounted by females after vaccination against SARS-CoV-2. 35, 37 Further, studies on the morbidity/mortality relationship due to SARS-CoV-2 infection between sexes found that males have three times higher probability of requiring intensive care unit admission and higher odds of mortality. 38 While these studies point to the increased risk and mortality among males, the overall percentage decline of Ab titers identified post-second dose vaccination indicates the need for boosters regardless of sex.

Infection with SARS-CoV-2 elicits a humoral immune response via production of immunoglobulins targeting the spike, nucleocapsid, as well as other viral proteins. 39 This translates in detectable Ab titers before SARS-CoV-2 mRNA vaccine administration among previously infected individuals, and significantly higher Ab levels after the first dose compared to those with no history of prior infection. 39 However, Ab titers measured after the second vaccine dose report varying trends ( Figure 5 ). Some studies reported that seropositive groups continue to have increased Ab levels compared to seronegative groups, while others reported that there is no significant difference between the two groups. [40] [41] [42] [43] [44] [45] These disparities in trend are conveyed in the rate of decline of Ab titers at 5-6 months after full immunization compared to peak levels. Among the four journal articles included in this study, two reported that seropositive groups had a larger percentage decline in Ab titers from peak compared with seronegative groups. 10, 12 This is possibly due to higher peak values making Ab catabolism more pronounced in seropositive groups. 12 Another possible explanation is due to timing, as seropositive groups reach peak Ab titers right after the first dose. Studies have observed that a second vaccine dose in seropositive groups does not significantly boost antibody titers higher, therefore these groups start their decline from peak much earlier than seronegative groups, who reach peak levels only after the second dose. 39 

In this systematic review, we characterized the substantial decline in

Abs at approximately 6 months after COVID-19 mRNA vaccinations.

To date, several studies identified a significant correlation between the time-dependent waning of Ab levels and an increased risk for breakthrough infections. 47, 48 In addition to the rise of SARS-CoV-2 variants of concern (VoC), like the Delta and more recently the Omicron variant, studies also suggest a correlation between cold weather and an increase in COVID-19 cases. 49 This is consistent with the established association between the circulation of respiratory viruses and climatic factors, displaying a peak incidence in the winter months. 49 33 Hence, even with the same rate of decline in humoral immunity post second dose mRNA vaccination as observed in our study, their titers are consistently lower, and may in many cases be below adequate thresholds for protection. Thus, it is prudent to prioritize the elderly and those with comorbidities for booster administration in the coming months.

As evidence of waning Ab levels accumulates, several countries have expanded their vaccine coverage to include giving off booster doses to all adults after completion of primary vaccination. 51, 52 As such, the rate of confirmed infection and the rate of severe illness were lower by a factor of 11.3 and 19.5, respectively, in the group that received the booster vaccine. 53 A secondary analysis had also shown that the rate of confirmed infection at least 12 days after booster administration was lower than the rate after 4-6 days by a factor of 5.4. 53 Further research is needed to understand the kinetics of antibody responses after vaccine boosters and to determine if a similar rate of decline is seen following adjunctive doses as observed with initial vaccination regimen.

In conclusion, our findings show that the levels of protective Abs significantly and consistently decline 6-8 months after the second dose of anti-SARS-CoV-2 mRNA vaccines regardless of age, sex, baseline serostatus, and comorbidities. This supports that the rate of Ab decline is mostly independent of patient-related factors and peak Ab titer achieved after the second mRNA dose, but instead mainly a function of time and Ab class/molecular target, with some variability arising from the sensitivity of the immunoassay. 54 Given this information, it may then be possible to predict the decline in Ab levels over time to an insufficient titer, based only on the patient's peak Ab titer (~4 weeks after the second dose for seronegative patients), and thus identify in advance the optimal time when a booster vaccine dose should be indicated without the need for serial serologic monitoring. Such a strategy should be investigated for those who are likely to be low responders or at high risk of breakthrough infection. 55 

The authors declare no conflicts of interest.

All the authors cited in the manuscript had substantial contributions to the concept and design, the execution of the work, or the analysis and interpretation of data; drafting or revising the manuscript, and have read and approved the final version of the paper. 

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How to cite this article: Notarte KI, Guerrero-Arguero I

Characterization of the significant decline in humoral immune response six months post-SARS-CoV-2 mRNA vaccination: a systematic review

The peer review history for this article is available at https://publons. com/publon/10.1002/jmv.27688