What Constitutes Protective Immunity Following Yellow Fever Vaccination? Part 3

5. YF Prevention

There is a safe and effective vaccine against YF which was first developed in 1937 using a live attenuated YF virus strain (17D), with the subsequent production of YF vaccine using sub-strains (17D-204, 17DD, and 17D-213) of 17D [1,23]. 

Recently, many people have had some concerns about the new coronavirus vaccine, and there are even rumors that vaccination will cause memory loss. However, these claims have no scientific basis. On the contrary, scientific research shows that vaccination does not negatively affect memory, but may protect us from disease and even strengthen our body's immunity.

Vaccines are a very effective way to prevent disease by allowing our bodies to make antibodies to fight off disease. By injecting vaccines, we can activate the body's immune system and allow the body to produce antibodies against certain diseases, thus greatly reducing the risk of illness. Especially under the current epidemic situation, vaccination against COVID-19 plays a very important role in preventing the spread of the virus, protecting one's health, and maintaining social stability.

At the same time, vaccination does not hurt memory. If we don't get vaccinated, we may be suffering from a disease that affects our memory. Illness affects our physical health, as well as our thinking and cognitive abilities. Vaccination can effectively prevent diseases and keep our bodies and brains healthy.

Therefore, we should actively get vaccinated to protect ourselves and those around us. At the same time, we should also pay attention to maintaining good living habits, including a good diet, adequate sleep, moderate exercise, etc., to maintain our physical and mental health. Through these efforts, we can live healthier, happier lives without worrying about vaccines negatively affecting our memory. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because Cistanche deserticola is a traditional Chinese medicinal material that has many unique effects, one of which is to improve memory. The efficacy of Cistanche deserticola comes from the multiple active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health through a variety of pathways.

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17D was developed by passaging the virulent strain (Asibi) in rhesus macaques, mouse, and chicken embryos causing mutations in genes encoding for both structural and non-structural proteins leading to the loss of its virulence [24]. 

The E protein of the 17D contains most of the mutations compared to other viral proteins, and given that E protein is responsible for viral attachment, and fusion and is considered a major target for antibodies, mutations in this protein play a significant role in the attenuation of 17D [8,24]. 

The vaccine is administered intramuscularly or subcutaneously to adults traveling to endemic areas or periodically in response to outbreaks, and to children (>nine months of age) through routine childhood immunization, with 80% and 100% of the vaccinees developing nAbs 10 days and one month post-immunization, respectively [21,25]. 

There has been no difference reported in safety and protective immunity when the vaccine is administered either intradermally or subcutaneously [26]. 

Given evidence that the single primary dose of YF vaccine can provide lifelong immunity, a booster dose, which was previously given at an interval of 10 years from the primary dose, is no longer needed except among at-risk populations such as those who are immunocompromised or immunosuppressed [1]. 

Population YF vaccination coverage of >80% is recommended by the WHO to prevent and control outbreaks, however, YF vaccine coverage remains too low to prevent outbreaks, especially in highly urbanized areas [5]. 

With the recent outbreaks, there is an increasing need to expand YF vaccine stocks since the current supply of YF vaccine is insufficient to provide effective coverage during outbreaks [1,4,21]. 

As a response, the WHO has recommended the use of fractional doses which have been used to control epidemics in the Democratic Republic of Congo and South America, and studies have reported equivalent immunogenicity to that of the standard full dose [1,27,28]. However, immune responses to fractional doses of the YF vaccine are yet to be fully understood.

6. Quantity and Quality of YF Vaccine-Induced Immune Response

YF vaccine induces several effector arms of the innate and adaptive immune response [29-34. The early innate immune response to the YF vaccine can offer protection from virulent viruses and it also determines the strength and quality of the adaptive immune response [35]. Upon vaccination, 17D infects dendritic cells (DC), where minimal transient viral replication occurs [35,36]. 

Multiple Toll-like receptors (TLR2, TLR7, TLR8, and TLR9)on these cells and their subsets (myeloid and plasmacytoid) become activated leading to the production of pro-inflammatory cytokines (including interferon-alpha) which induce an antiviral response, stimulates a mixed T helper 1- and 'T helper 2 cell profile, and regulate B-cell responses [35,36]. DC also acts as antigen-presenting cells. They process and present internalized 17D epitopes to 'T cell receptors [35].

A recent study reported that YFV-specific memory CD 4+ T cells were present among unvaccinated individuals, however, with exposure to the virus/viral antigens, rare and more responsive T cells become recruited against the novel pathogen whereas pre-existing YFV-specific T cell populations with low clonal diversity undergo limited expansion [14]. 

Other studies have shown that the YF vaccine elicits robust early effector CD 4+ T cell responses with YFV-specific memory T cells being readily detected in subjects examined years after vaccination although with a wide range of frequencies (i.e., 0–100 cells per million CD 4+ T cells) [38,39,41–43]. 

After approximately 14 days post-vaccination, total CD 8+ T cells become activated, undergo clonal expansion, and differentiate into effector CD 8+ T cells which are distributed throughout the body to control for infection [38,44]. 

Effector CD 8+ T cells then differentiate to central memory and effector memory T cells (i.e., within four weeks post-vaccination) and remain detectable for decades [38,44], corroborated by a study which reported the possibility of sufficient long-term immunity after vaccination given the presence of functionally competent YF-specific memory T-cell pool 18 years post-vaccination [29]. 

Similarly, memory T cells remained detectable eight years post-vaccination with fractional doses of YF vaccine and these markers of cellular immunity positively correlated with nAbs levels. 

These cellular immune responses elicited by the fractional dose were at comparable levels to those elicited by the standard full dose of the YF vaccine [45]. There have been other conflicting data on cellular immunity to the YF vaccine. For example, studies have reported a decline in the level of effector memory CD4+, CD8+ T cell, and interferon- γ+ CD8+ T cells after primary vaccination, suggesting the need for booster vaccination [30,46].

6.2. Humoral Immunity

IgM mediates the early memory B cell response, which appears ~7–14 days following primary vaccination and can be detected up to 1–4 years post-vaccination [47]. The persistence of IgM has been linked to earlier onset viremia or higher nAbs titers [35,47]. On the other hand, IgG develops slowly (i.e., within the first month of vaccination) and can last up to 40–60 years post-vaccination [15,35], (Figure 5).
A recently published review has summarised humoral immunity in adults and children who have received full-dose vaccination [1]. Seropositivity rates among adults were>90% and ranged between 67% and 97%, within five years and ≥10 years post-vaccination, respectively, whereas in children, seropositivity rates ranged between 87% and 100% and between 28% and 76% within the first year and≥1–10 years post-vaccination, respectively [29,32–34,48–53]. Compared to adults, children seroconvert at a lower rate and have a larger decline in nAbs titers over the years suggesting the need for a booster dose of the YF vaccine in this age group. Nevertheless, the data available is scarce, and these findings cannot be generalized as the studies were limited and heterogeneous concerning how samples and vaccines were handled, the type of vaccine strain used, and different seropositivity cut-off points employed [1,31]. 

Regarding immunogenicity following vaccination with fractional doses of the YF vaccine, participants who received 1/100th, 1/50th, 1/10th, 1/5th, and 1/3rd of YF vaccine doses had seroconversion rates of ≥87%, ≥92%, ≥97%, ≥95% and ≥98%, respectively, which lasted between eight and 10 years post-vaccination. These seroconversion rates were relatively similar to those of participants receiving the standard full dose which was at ≥95% [54]. nAbs are considered the primary correlate of protection following YF vaccination. 

Published data on immune responses following YF vaccination have only quantified YF virus-specific nAbs using eithemicroneutralizationon test for detection of antibodies or PRNT, reporting either 90% PRNT, 80% PRNT, or 50% PRNT titers, with titers of 1 in 10 or higher considered a surrogate of protection [1,31]. While PRNT anmicroneutralizationon assays are essential in evaluating antibodtiterre anneutralizationon activity post-vaccination, they only assess limited humoral characteristics [55]. Furthermore, it has been shown that some vaccinated individuals who do not develop nAbs can develop p secondary immune response with re-vaccination or exposure to infection [56,57]. 

The simultaneous binding of the fragment antigen-binding (Fab) regions of antibodies to foreign antigens expressed on the surfaces of pathogens or infected cells, and of the fragment crystallizable (Fc) portion of the antibody to Fc gamma receptors (FcγRs) that are expressed by immune cells, trigger antibody effector functions that eliminate pathogens such antibody-dependent cellular cytotoxicity (ADCC) antibody-dependent cellular phagocytosis (ADCP), an antibody-dependent complement deposition (ADCD) [58] (Table 1). 

Antibodies with these functions may or may not have neutralizing activity and can recognize other pathogen proteins that are not involved in host-cell entry [55]. A study assessing the immune response in mice vaccinated with a chimeric Japanese Encephalitis vaccine (JE-CVax) and challenged with lethal YFV, showed that JE-Cvax could induce YFV-specific antibodies mediating ADCC in a dose-dependent manner [59]. Nevertheless, there are no studies that have characterized YF vaccine-induced antibody effector function in humans. 

The capacity of antibodies to induce effector functions is also dependent on antibody isotype, subclass, and glycosylation [55]. Some of the vaccine-induced polyclonal antibodies could either work collaboratively resulting in a more functional Fc effector profile or may compete against each other thus hindering Fc effector functions. This has been described in HIV vaccine trials where VAX003 vaccination resulted in elevated levels of IgG4 subclass antibodies, which have weak immune responses, competing for antigen occupancy thus blocking Fc effector functions, whereas RV144 vaccination resulted in elevated levels of IgG3 subclass antibodies, which elicited strong immune responses and also could induce ADCC, ADCP and antibody-mediated activation of NK cells [55]. 

Antibody glycosylation determines specific antibody effector functions by altering the structure of the antibody Fc region (through the addition of N-glycan at specific asparagine residues on the Fc section) [60,61]The majority of infection-associated immune profilinhasve focused on IgG Fc glycosylation and there is evidence to show that IgG Fc glycosylation can be altered following influenza and tetanus vaccination, and thus plays a critical role in shaping protective immunity [61].

While the YF vaccine is considered highly successful with high seroconversion rates, other factors have been associated with lower seroconversion rates or vaccine failures. These include age (i.e., the premature waning of protection among vaccinated infants between the ages of nine and 12 months and the elderly >60 years), exposure to other childhood vaccines such as measles, mumps, and rubella (MMR), and geographical regions especially YF endemic countries [1,66,67]. A study showed that after vaccination with YF17D, individuals living in endemic areas had impaired immune responses with decreased persistence compared to those living in non-endemic areas [67].

7. Research Gaps

There are no studies that have provided a detailed characterization of YF vaccine-induced protective immunity in the absence or presence of nAbs. As demonstrated in studies evaluating Malaria, HIV, and SARS-CoV-2 vaccine candidates or immune responses following infection, apart from neutralization, antibodies can also engage FcγRs or the complement system to induce a range of Fc-effector functions which have robustly predicted protection from infection [55,68,69]. Systems serology for the evaluation of vaccine-induced immune responses is not done routinely despite its ability to provide a comprehensive approach to assess the diversity of humoral immune responses, which can help inform vaccine development, delivery, and dosing. 

The assessment of biophysical antibody characteristics following YF vaccination and associated risk factors including age, host genetics, geographical settings (i.e., endemic vs. non-endemic areas), and coinfections, could help provide a comprehensive landscape of the humoral immune response and a better understanding of correlates of protective immunity. Furthermore, with the current shortage of YF vaccine and the drive towards using fractional dosing-whose evidence has been based solely on quantified titers of YF virus-specific neutralizing antibodies [54]-data evaluating YF vaccine-induced cellular immunity using this dose regimen are needed. T-cell and memory B-cell responses are predictive of the quality and quantity of the humoral immune response. 

However, it remains unclear whether and how cellular immunogenicity is protective against YF virus infection. Data describing the magnitude and duration of cellular immune response, especially with fractional vaccine doses as well as the correlation between cellular and humoral immune response following this vaccination regimen are needed. In addition, a better understanding of both humoral and cellular immunity following vaccination might also help predict long-term immune responses without having to obtain data over a long duration of follow-up.

Author Contributions: J.M., writing-original draft preparation; J.M., D.K., T.L., and G.M.W., writing- review and editing. All authors have read and agreed to the published version of the manuscript.

Funding: J.M., T.L., and G.M.W. are supported by a Wellcome Trust grant [grant number 220991/Z/20/Z]. D.K. and G.M.W. are also supported by an Oak Foundation fellowship and a Wellcome Trust grant [grant number 203077_Z_16_Z]. TL is a Jenner Investigator.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Data Availability Statement: No new data were created or analyzed in this study. Data sharing does not apply to this article.

Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the writing of the review.

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